
Glass. 
Book. 



COPYRIGHT DEPOSIT 



THE CHEMISTRY AND ANALYSIS 
OF DRUGS AND MEDICINES 



BY 

HENRY C. FULLER, B.S. 

In Charge of the Division of Drug and Food Products, 

The Institute of Industrial Research, 

Washington, D. C. 



NEW YORK 
JOHN WILEY & SONS, Inc. 
London: CHAPMAN & HALL, Limited 
1920 



"The use in this volume of certain portions of the text of the United 
States Pharmacopoeia is by virtue of permission received from the Board 
of Trustees of the United States Pharmacopoeial Convention. The said 
Board of Trustees is not responsible for any inaccuracy of quotation nor 
for any errors in the statement of quantities or percentage strengths." 

"Permission to use for comment parts of the text of the National 
Formulary, Fourth Edition, in this volume has been granted by the 
Committee on Publication by the authority of the Council of the 
American Pharmaceutical Association." 






Copyright, 1920, by 
HENRY C. FULLER 




* 



\ 

DEC 27 1920 

©CU604716 



PRESS OF 

BRAUNWORTH L CO. 

BOOK MANUFACTURERS 

BROOKLYN, N. V. 



CONTENTS 



INTRODUCTION 

Part I 

GENERAL METHODS AND CRUDE DRUG ASSAYS 

CHAPTER I 

PAQB 

General Methods 1 

CHAPTER II 
Crude Drug Assays 23 



Part II 

ALKALOIDAL DRUGS, ALKALOIDS AND MEDICINALLY 
ALLIED SUBSTANCES 

CHAPTER III 
Definition and General Methods of Separation and Identification 71 

CHAPTER IV 

Alkaloids Derived from Pyridin 82 

CHAPTER V 
Alkaloids Derived from Pyrrolidin 100 

CHAPTER VI 
Alkaloids Derived from Quinolin 149 

CHAPTER VII 

Alkaloids Derived from Isoquinolin 183 

iii 



IV CONTENTS 

CHAPTER VIII 

PAGE 

Alkaloids which Probably Contain a Pyridin Nucleus 250 

CHAPTER IX 
Alkaloids with no Pyridin Nucleus and Those of Unknown Composition. 281 



Part III 

GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 
CONTAINING PRINCIPLES OTHER THAN ALKALOIDS 

CHAPTER X 
Glucosides 309 

CHAPTER XI 
Purgative Drugs 360 

CHAPTER XII 
Miscellaneous Acting Drugs 391 

CHAPTER XIII 
Botanical Drugs 414 

CHAPTER XIV 
Gums and Resins 460 



Part IV 

ORGANIC SUBSTANCES OTHER THAN ALKALOIDS 
AND GLUCOSIDES 

CHAPTER XV 

Hydrocarbons — Alcohols — Ethers 517 

CHAPTER XVI 

Aldehydes and Ketones 570 

CHAPTER XVII 
Organic Acids — Aliphatic Series 624 



CONTENTS V 

CHAPTER XVIII 

PAGE 

Organic Acids — Aromatic Series 658 

CHAPTER XIX 

Ethereal Salts — Phenols 727 

CHAPTER XX 
Synthetic Organic Nitrogen Compounds, Amines, Diamines, Amides 790 

CHAPTER XXI 

Anilides and Phenetidines 83 1 

CHAPTER XXII 
Organic Arsenic Compounds 873 

CHAPTER XXIII 

Proteins and Digestives 884 

CHAPTER XXIV 
Oils 913 

Part V 
INORGANIC SECTION 

CHAPTER XXV 
Methods of Identification 937 

CHAPTER XXVI 

Non-Metals and Their Compounds 940 

CHAPTER XXVII 

Metals and their Compounds 970 

Tables 1C33 

Index 1050 



INTRODUCTION 



Whoever has taken up an investigation of drugs and medicines, 
whether in the line of analysis or research, must have been impressed 
with the fact that there has been no individual publication dealing with 
analytical procedures applicable to the subject as a whole. 

The analyst could turn to the Pharmacopoeia and National Formulary 
for methods of assaying and testing the official drugs, and to other works 
such as Autenreith and Warren's " Detection of Poisons," " New and 
Non-Official Remedies " published by the American Medical Association, 
and the publications of the Association of Official Agricultural Chemists, 
where he would find information and perhaps methods applicable to 
certain classes of drugs and medicinal agents, but there has been no 
general analytical work embracing this branch of chemistry. The food 
analyst could turn to Leach's " Food Inspection and Analysis," and there 
find complete the latest methods for solving his analytical problems, but 
the drug analyst was less fortunate, and when presented with a problem 
of analysis outside the usual run of drug assaying, there was involved a 
long search through the available text books, technical journals, and 
official publications before a satisfactory procedure was found, if any existed. 
The work in hand has been published in order to remedy this situation. 
The material for it has been collected during the past seventeen years, 
and has been arranged in a way which it is believed will be found con- 
venient to the worker who is handling miscellaneous analytical investi- 
gations. 

Problems of analysis of drugs and medicines are many and varied. 
Those most frequently met with may be grouped as follows: 

The assaying of individual crude drugs and medicinal chemicals; 
The analysis of mixtures for one or more essential ingredients; 
The determination of the character and amounts of the compo- 
nents of a medicine, either for purposes of duplication, or for the 
basis of a court proceeding; 
The testing of individual substances for their identity and purity; 
The separation and identification of the hitherto unknown consti- 
tuents of crude drugs; 
The identification of small quantities of toxic principles. 



viii INTRODUCTION 

The subject matter in this work has been arranged in general in accord- 
ance with its chemical relationship, although in that portion dealing with 
organic substances the sequence in which one group follows another in 
theoretical chemistry has not been followed. In the groups themselves 
some substances have been' discussed simultaneously with those with which 
they are medicinally allied, even though they may not be related to them 
chemically. For instance, it is obviously more comprehensive to include 
all of the local anesthetics under the chapter on "Cocain" than to scatter 
them through the various groups of organic compounds under which 
they would fall because of their chemical relationship. 

By far the larger proportion of the number of the individual drugs 
and remedial agents belong to the class of organic substances. In the 
general arrangement the natural drugs and their derivatives have been 
considered first, then follows the individual organic substances, including 
most of the so-called " synthetics," and lastly the inorganic drugs. 

Those characteristics of the different substances valuable for their 
analytical significance have been detailed, many new, important and hith- 
erto obscure reactions have been recorded, and wherever reliable quanti- 
tative methods of determination and separation could be found, they 
have been described. 

In the treatment of the individual drugs and medicinal agents con- 
siderable space has been devoted to detailing the character of the remedies 
in which they commonly occur, and the combinations usually found in 
practice. Knowledge of this kind is of great aid to the analyst, and will 
often save a vast amount of unnecessary labor when he is working with 
an unknown mixture. As a matter of fact, if the analyst has at his dis- 
posal the latest catalogues of the large pharmaceutical houses, he will 
often obtain valuable assistance in arriving at the probable composition 
of a remedy, once he knows for what purpose it is to be used, and the 
identity of one or more of the essential ingredients. 

A section of the work has been devoted to some general determi- 
nations which are often necessary in analyzing galenicals, and for the con- 
venience of the drug assayist a section has been given over to drug assays 
in which are assembled all of the reliable representative methods available 
for analyzing crude drugs. 

In the various groups, especially in the organic section, references 
will be found to many substances which are not used medicinally, but 
which, by reason of their properties, are closely related to those having 
direct connection with the general subject. These individuals have 
been noted because it often happens, especially when working up a court 
case, that the chemist finds it necessary to refresh his knowledge con- 
cerning the members of a given series of organic substances other than 
the particular one which will figure in the case. 



INTRODUCTION IX 

No attempt has been made in general to go into the description of 
the botanical drugs from the standpoint of the pharmacognosist. To 
have consumed space with their descriptions would only have duplicated 
such special works on the subject, as Kraemer's " Botany and Pharma- 
cognosy." 

Data for this work have been drawn freely from authorities who have 
handled special subjects, and in each instance due reference and credit 
have been given. Much material has appeared in the literature during 
the past twenty years ; practically all of this has been reviewed, and that 
which was reliable and essential has been quoted. The assembling and 
classification of all this material, and the testing out of the methods, 
have involved considerable research, but it is believed that the object in 
view justified the endeavor, and that there has been evolved a work which 
will be greatly appreciated by those concerned with the inspection and 
analysis of drugs and medicines. 



Part I 

GENERAL METHODS AND CRUDE 
DRUG ASSAYS 



CHAPTER I 
GENERAL METHODS 

It is almost a waste of time to begin the quantitative analysis of a 
medicinal product until one has determined by carefully performed quali- 
tative investigation the nature of the substances present. In food analysis 
one can often determine the percentages of moisture, ash, nitrogen, starch, 
rotatory power before and after inversion, the presence or absence of pre- 
servatives and then interpret his results. Not so with drug analysis. 
Except in cases where the worker has to deal with extracts or substances 
containing but one ingredient, each preparation offers a problem by 
itself and often a dozen samples containing the same single ingredient, 
put out by a dozen different firms, will require different procedures owing 
to the difference in pharmaceutical make up. 

There are, however, certain general tests which must be applied to 
large groups of substances regardless of their composition, and for conven- 
ience they have been detailed at this point. 

In the cases of all liquid preparations, the specific gravity and alcohol 
should be estimated; in both liquids and solid medicinal agents the total 
non-volatile matter, ash, and sugar determined as a guide and check in 
arriving at the final composition, and the presence and amount of arsenic 
should be established. 

SPECIFIC GRAVITY 

This datum should be determined with an accurate pycnometer at 
a convenient temperature, such as 15.6° or 20° C. The result is an aid 
in the future determinations and obviates the weighing out of the sample 
if the measurements are made in accurately graduated flasks or pipettes. 



2 GENERAL METHODS AND CRUDE DRUG ASSAYS 

ALCOHOL 

If the sample contains but negligible quantities of volatile matter other 
than alcohol and water, the alcohol may be estimated by simple distil- 
lation and determining the amount from the specific gravity of the dis- 
tillate, which should be so regulated that it does not contain over 50 per 
cent of alcohol and for satisfactory results never more than 35 per cent, 
hence if the sample is suspected of containing over 50 per cent alcohol, 
it should be distilled and made up to twice its original volume. 

If the sample is acid and contains no free iodine, it sould be neutral- 
ized with alkali and the distillate should be subsequently tested with 
litmus to determine its alkalinity. In certain instances, when ammonium 
salts occur in mixtures containing alkaloids or alkaloid-bearing drugs, 
free ammonia will be disengaged, and the distillate must be neutralized 
with sulphuric or phosphoric acid and again distilled. 

If iodine be present, it can be fixed with sodium thiosulphate. 

The determination is made by filling to the mark an accurately gradu- 
ated 50-mil flask, observing the proper temperature at which the flask 
is graduated, and pouring the contents into the retort flask of a distilling 
apparatus; the flask is washed out with three portions of 15 to 20 mils 
of distilled water, pouring the water into the flask of the distilling appa- 
ratus. Distillation is then conducted into the flask in which the original 
measurement was made or one of double its capacity, having it surrounded 
with ice water, until it is about three-quarters full, when it is removed and 
made up with distilled water to volume, the temperature being adjusted 
to that at which the original measurement was made. The specific gravity 
is determined at 15.6° or 20° C. by means of an accurate pycnometer, 
and from the figure obtained the alcoholic percentage determined from 
the standard table. 

When working with sarsaparilla, soapwort, or other solutions con- 
taining saponin-like bodies which produce frothing, a small amount of 
paraffin or petrolatum should be added to prevent the liquid from bubbling 
over into the receiver. With some mixtures it may prove more satis- 
factory to distill without attempting to prevent some of the bubbles from 
going over and then to conduct a second distillation. 

The presence of g ycerin has no effect on the accuracy of the method, 
for this substance does not come over with the distillate unless the con- 
centration of the glycerin solution is over 70 per cent. Acetanilid will 
distill in small amounts, but its presence in the distillate does not affect 
the accuracy of the method. 

If volatile oils, chloroform, ether, camphor, or like substances are 
present, the method must be modified by the principle advanced by 
Thorpe and Holmes 1 using petroleum ether and sodium chloride to salt 
i J. Chem. Soc, 1903, 83, 313. 



GENERAL METHODS 



ALCOHOLOMETRIC TABLE 
Temperature 15.56° C. 



Percentage by Volume 


Percentage by Weight 


Per 

Cent 
Vol. 


Corre- 
sponding 
Per Cent 

Weight 


Sp. Gr. 
App.* 
in Air 
15.56° 
15.56° 


Corr.f 
of Sp. Gr. 

for 
Barometer 
(100 mm.) 


Frac- 
tional^ 
Per Cent 


Per 
Cent 
Wt. 


Corre- 
sponding 
Per Cent 

Volume 


Sp. Gr. 

App.* 
in Air 

15.56° 
15.56° 


Corr.f 
of Sp. Gr. 

for 
Barometer 
(100 mm.) 


Frac- 
tional! 
Per Cent 


§o 


0.000 


1.00000 


0.000000 


0.0667 





0.000 


1.00000 


0.000000 


0.0532 


1 


0.795 


0.99850 


0.000000 


0.0680 


1 


1.257 


0.99812 


0.000000 


0.0543 


2 


1.593 


0.99703 


0.000000 


0.0690 


2 


2.510 


0.99628 


0.000000 


0.0565 


3 


2.392 


0.99558 


0.000001 


0.0714 


3 


3.758 


0.99451 


0.000001 


0.0588 


4 


3.194 


0.99418 


0.000001 


0.0730 


4 


5.002 


0.99281 


0.000001 


0.0610 


5 


3.998 


0.99281 


0.000001 


0.0746 


5 


6.243 


0.99117 


0.000001 


0.0641 


6 


4.804 


0.99149 


0.000001 


0.0781 


6 


7.479 


0.98961 


0.000001 


0.0671 


7 


5.612 


0.99021 


0.000001 


0.0813 


7 


8.712 


0.98812 


. 000002 


0.0680 


8 


6.422 


0.98898 


0.000002 


0.0833 


8 


9.943 


0.98665 


0.000002 


0.0700 


9 


7.234 


0.98778 


0.000002 


0.0840 


9 


11.169 


0.98523 


. 000002 


0.0719 


10 


8.047 


0.98659 


0.000002 


0.0855 


10 


12.393 


0.983S4 


0.000002 


0.0746 


11 


8.862 


0.98542 


0.000002 


0.0877 


11 


13.613 


0.98351 


0.000003 


0.0769 


12 


9.679 


0.98428 


0.000002 


0.0901 


12 


14.832 


0.98120 


0.000003 


0.0775 


13 


10.497 


0.98317 


0.000003 


0.0917 


13 


16.047 


0.97991 


0.000003 


0.0800 


14 


11.317 


0.98208 


0.000003 


0.0943 


14 


17.259 


97866 


0.000003 


0.0820 


15 


12.138 


0.98102 


0.000003 


0.0943 


15 


18.469 


0.97744 


0.000004 


0.0840 


16 


12.961 


0.97996 


0.000003 


0.0962 


16 


19.676 


0.97625 


0.000004 


0.0833 


17 


13.786 


0.97892 


0.000003 


0.0990 


17 


20.880 


0.97505 


0.000004 


0.0826 


18 


14.612 


0.97791 


0.000004 


0.1000 


18 


22.081 


0.97384 


0.000004 


0.0813 


19 


15.440 


0.97691 


0.000004 


. 1020 


19 


23.278 


0.97261 


0.000004 


0.0806 


20 


16.269 


0.97593 


0.000004 


0.1000 


20 


24.472 


0.97137 


. 000005 


0.0794 


21 


17.100 


0.97493 


0.000004 


0.0990 


21 


25.662 


0.97011 


0.000005 


0.0781 


22 


17.933 


0.97392 


0.000004 


0.0980 


22 


26.849 


0.96883 


. 000005 


0.0769 


23 


18.768 


0.97290 


0.000004 


0.0962 


23 


28.032 


0.96753 


0.000005 


0.0752 


24 


19.604 


0.97186 


0.000005 


0.0952 


24 


29.210 


0.96620 


0.000005 


0.0740 


25 


20.443 


0.97081 


0.000005 


0.0943 


25 


30.388 


0.96485 


0.00C006 


0.0719 


26 


21.285 


0.96974 


0.000005 


0.0926 


26 


31.555 


0.96346 


0.000006 


0.0694 


27 


22.127 


0.96866 


0.000005 


0.0909 


27 


32.719 


0.96202 


0.000006 


0.0667 


28 


22.973 


0.96756 


0.000005 


0.0893 


28 


33.879 


0.96052 


0.000006 


0.0649 


29 


23.820 


0.96644 


0.000005 


0.0877 


29 


35.033 


0.95898 


0.000007 


0.0633 


30 


24.670 


0.96530 


0.000005 


0.0862 


30 


36.181 


0.95740 


0.000007 


0.0613 



GENERAL METHODS AND CRUDE DRUG ASSAYS 



ALCOHOLOMETRIC TABLE— Continued 



Percentage by Volume 


Percentage bt Weight 


Per 
Cenl 
Vol. 


Corre- 
sponding 
Per Cent 

Weight 


Sp. Gr. 
App.* 
in Air 
15.56° 
15.56° 


Corr.t 
of Sp. Gr. 

for 
Barometei 
(100 mm.) 


Frac- 
tional:): 
Per Cent 


Per 
Cen1 
Wt. 


Corre- 
sponding 
Per Cent 
Volume 


Sp. Gr. 
App.* 
in Air 
15.56° 
15.56° 


Corr.t 
of Sp. Gr. 

for 
Barometer 
(100 mm.) 


Frac- 
tional^ 
Per Cent 


31 


25.524 


0.96414 


o.oooooe 


0.0820 


31 


37.323 


0.95577 


0.000007 


0.0595 


32 


26.382 


0.96292 


0.000006 


0.0787 


32 


38.459 


0.95408 


. 000007 


0.0578 


33 


27.242 


0.96165 


0.000006 


0.0775 


33 


39.590 


0.95236 


0.000007 


0.0565 


34 


28.104 


0.96036 


0.000006 


0.0752 


34 


40.716 


0.95058 


000008 


0.0556 


35 


28.971 


0.95903 


0.000006 


0.0725 


35 


41.832 


0.94878 


0.000008 


0.0546 


36 


29.842 


0.95765 


0.000007 


0.0704 


36 


42.944 


0.94696 


0.000008 


0.0538 


37 


30.717 


0.95623 


0.000007 


0.0685 


37 


44.050 


0.94509 


. 000009 


0.0521 


38 


31.596 


0.95477 


0.000007 


0.0668 


38 


45 . 149 


0.94317 


0.000009 


0.0515 


39 


32.478 


0.95326 


. 000007 


0.0649 


39 


46.242 


0.94123 


0.000009 


0.0508 


40 


33.364 


0.95172 


0.000007 


0.0633 


40 


47.328 


0.93926 


. 000010 


0.0498 


41 


34.254 


0.95014 


0.000008 


0.0617 


41 


48.407 


0.93725 


0.000010 


0.0488 


42 


35 . 150 


0.94852 


. 000008 


0.0600 


42 


49.480 


0.93520 


0.000010 


0.0485 


43 


36.050 


0.94687 


0.000008 


0.0588 


43 


50.545 


0.93312 


0.000011 


0.0476 


44 


36.955 


0.94517 


0.000009 


0.0578 


44 


51.605 


0.93102 


0.000011 


0.0474 


45 


37.865 


0.94344 


0.000009 


0.0565 


45 


52.658 


0.92891 


0.000011 


0.0469 


46 


38.778 


0.94167 


. 000009 


0.0552 


46 


53.705 


0.92678 


0.000012 


0.0467 


47 


39.697 


0.93986 


0.000009 


0.0541 


47 


54.746 


0.92464 


0.000012 


0.0461 


48 


40.622 


0.93801 


. 000010 


0.0526 


48 


55.780 


0.92247 


0.000012 


0.0461 


49 


41.551 


0.93611 


0.000010 


0.0518 


49 


56.808 


0.92030 


0.000013 


0.0457 


50 


42.487 


0.93418 


0.000010 


0.0510 


50 


57.830 


0.91811 


0.000013 


0.0455 


51 


43.428 


0.93222 


0.000011 


0.0503 


51 


58.844 


0.91591 


0.000013 


0.0446 


52 


44.374 


0.93023 


0.000011 


0.0498 


52 


59.851 


0.91367 


0.000014 


0.0444 


53 


45.326 


0.92822 


0.000011 


0.0488 


53 


60.854 


0.91142 


0.000014 


0.0444 


54 


46.283 


0.92617 


. 000012 


0.0483 


54 


61.850 


0.90917 


0.000014 


0.0442 


55 


47.245 


0.92410 


. 000012 


0.0478 


55 


62.837 


0.90691 


. 000015 


0.0441 


56 


48.214 


0.92201 


0.000012 


0.0474 


56 


63.820 


0.90464 


0.000015 


0.0441 


57 


49.187 


0.91990 


0.000013 


0.0463 


57 


64.798 


0.90237 


0.000015 


0.0441 


58 


50.167 


0.91774 


0.000013 


0.0457 


58 


65.768 


0.90010 


0.000016 


0.0437 


59 


51.154 


0.91555 


0.000013 


0.0452 


59 


66.732 


0.89781 


. 000016 


0.0435 


60 


52.147 


0.91334 


0.000014 


0.0446 


60 


67.690 


0.89551 


0.000016 


0.0433 


61 


53.146 


0.91110 


0.000014 


0.0439 


61 


68.641 


0.89320 


0.000017 


0.0431 


62 


54.152 


0.90882 


0.000014 


0.0437 


62 


69.586 


0.89088 


0.000017 


0.0431 


63 


55.165 


0.90653 


0.000015 


Q.0435 


63 


70.523 


0.88856 


0.000017 


0.0427 


64 


56.184 


0.90423 


0.000015 


0.0429 


64 


71.455 


0.88623 


0.000018 


0.0426 


65 


57.208 


0.90190 0.000015 0.0426 


65 


72.380 


0.88388 


0.000018 


0.0426 



GENERAL METHODS 
ALCOHOLOMETRIC TABLE— Continued 





Percentage by Volume 






Percentage by 


Weight 




Per 
Cent 
Vol. 


Corre- 
sponding 
Per Cent 

Weight 


Sp. Gr. 
App.* 

in Air 
15.56° 
15.56° 


Corr.t 
of Sp. Gr. 

for 
Barometer 
(100 mm.) 


Frac- 

tionalj 

Per Cent 


Per 

Cent 
Wt. 


Corre- 
sponding 
Per Cent 

Volume 


Sp. Gr. 
App.* 
in Air 
15.56° 
15.56° 


Corr.t 
of Sp. Gr. 

for 
Barometer 
(100 mm. 


Frac- 
tional % 
Per Cent 


66 


58.241 


0.89955 


0.000016 


0.0420 


66 


73.299 


0.88153 


0.000019 


0.0426 


67 


59.279 


0.89717 


0.000016 


0.0410 


67 


74.211 


0.87918]0. 000019 


0.0426 


68 


60.325 


0.89477 


0.000016 


0.0408 


68 


75.117 


0.87683 0.000019 


0.0422 


69 


61.379 


0.89232 


0.000017 


0.0407 


69 


76.016 


0.87446 


0.000020 


0.0422 


70 


62.441 


0.88986 


0.000017 


0.0403 


70 


76.909 


0.87206 


0.000020 


0.0418 


71 


63.511 


0.88738 


0.000018 


0.0395 


71 


77.794 


0.86970 


0.000021 


0.0417 


72 


64.588 


0.88485| 0.000018 


0.0392 


72 


78.672 


0.86730 


0.000021 


0.0417 


73 


65.674 


0.88230 0.000019 


0.0389 


73 


79.544 


0.86490 


0.000021 


0.0417 


74 


66.768 


0.87973 


0.000019 


0.0385 


74 


80.410 


0.86250 


0.000022 


0.0413 


75 


67.870 


0.87713 


0.000019 


0.0380 


75 


81.269 


0.86008 


0.000022 


0.0413 


76 


68.982 


0.87450 


0.000020 


0.0376 


76 


82.121 


0.85766 


0.000022 


0.0413 


77 


70.102 


0.87184 


0.000020 


0.0370 


77 


82.967 


0.85524 0.000023 


0.0412 


78 


71.234 


0.86914 


0.000021 


0.0365 


78 


83.805 


0.852810.000023 


0.0403 


79 


72.375 


0.86640 


0.000021 


0.0362 


79 


84.636 


0.85033 0.000024 


0.0408 


80 


73.526 


0.86364 


0.000021 


0.0357 


80 


85.459 


0.84788 0.000024 


0.0403 


81 


74.686 


0.86084 


0.000022 


0.0352 


81 


86.275 


0.84540 0.000024 


0.0402 


82 


75.858 


0.85800 


0.000022 


0.0350 


82 


87.083 


0.842910.000025 


0.0402 


83 


77.039 


0.85514 


0.000023 


0.0344 


83 


87.885 


0.84042 0.000025 


0.0398 


84 


78.233 


0.85223 


0.000023 


0.0337 


84 


88.678 


0.83791 


0.000025 


0.0394 


85 


79.441 


0.84926 


0.000024 


0.0331 


85 


89.464 


0.83537 


0.000026 


0.0392 


86 


80.662 


0.84624 


0.000024 


0.0326 


86 


90.240 


0.83282 


0.000026 


0.0391 


87 


81.897 


0.84317 


0.000025 


0.0322 


87 


91.008 


0.83026J 0.000027 


0.0386 


88 


83 . 144 


0.84006 


0.000025 


0.0314 


88 


91.766 


0.82767 0.000027 


0.0377 


89 


84.408 


0.83688 


0.000026 


0.0307 


89 


92.517 


0. 82502^. 000028 


0.0380 


90 


85.689 


0.83362 


0.000026 


0.0300 


90 


93.254 


0.82239:0.000028 


0.0372 


91 


86.989 


0.83029 


0.000027 


0.0291 


91 


93.982 


0.81970 0.000028 


0.0367 


92 


88.310 


0.82685 


0.000027 


0.0282 


92 


94.700 


0.816970.000029 


0.0362 


93 


89 . 652 


0.82330 


0.000028 


0.0272 


93 


95.407 


0.814210.000029 


0.0358 


94 


91.025 


0.81963 


0.000028 


0.0262 


94 


96.103 


0.81142 


0.000030 


0.0353 


95 


92.423 


0.81581 


0.000029 


0.0252 


95 


96.787 


0.80859 


0.000030 


0.0348 


96 


93.851 


0.81184 


0.000030 


0.0240 


96 


97.457 


0.80572 


. 000030 


0.0342 


97 


95.315 


0.80769 


0.000030 


0.0229 


97 


98.117 


0.80280 0.000031 


0.0334 


98 


96.820 


0.80333 


0.000031 


0.0214 


98 


98.759 


0.799810.000031 


0.0328 


99 


98.381 


0.79865 0.000031 


0.0200 


99 


99.386 


0.79676 0.000032 


0.0322 


100 


100.000 


0.79365,0.000032 




100 


100.000 


0.79365 0.000032 





6 GENERAL METHODS AND CRUDE DRUG ASSAYS 

out the volatile ingredients. Unless the mixture contains considerable 
fixed residue such as mineral salts, sugar, or drug extractive, the proced- 
ure can be carried out on the original sample, but if these are present in 
marked quantity a preliminary distillation should be made. Then the 
solution is transferred to a separator, diluted with water if necessary until 
the alcoholic content is not over 25 per cent, excess of solid sodium chloride 
added, and shaken out three times with about one-fourth its volume of 
low-boiling petroleum ether. The petroleum ether washings are collected 
in another separator, washed with saturated salt solution, the latter added 
to the main liquid and the whole distilled. 

NON-VOLATILE MATERIAL AND ASH 

The non-volatile material can often be determined in the residue 
remaining in the distilling flask from the alcohol determination unless 
it was necessary to manipulate the solution in some way before carrying 
out the distillation. In case this is not feasible 10-25 mils of the original 
sample are used for the determination, measurement being made with 
an accurate pipette or graduated flask, the sample washed into a small 
porcelain dish and evaporated over the steam bath until there is appar- 
ently no further diminution in volume, and then transferred to a drying 
oven and exposed to the heat of 100° C. for five hours. The dish should be 
cooled in a desiccator and weighed rapidly, no attempt being made to go 
beyond the third decimal, as most of these residues are hygroscopic. 
This method will give one an idea of the amount of non-volatile material 
present. The water will be practically all eliminated in this time, and 
while continued heating will cause a further loss in weight, it is due to 
the expulsion of other volatile substances, the breaking down of sugar, 
the gradual volatilization of glycerin, etc. In the case of some mixtures 
the determination of non-volatile material by this method will prove of 
little value; for instance, if one is dealing with a headache mixture con- 
taining acetanilid, the latter will volatilize. Such preparations, after 
the water is nearly all driven off on the steam bath, should be allowed to 
dry for ten or twelve hours in a vacuum desiccator over sulphuric acid 
or calcium chloride. 

ASH 

After weighing the residue in the above determination, it should be 
carefully burned and the ash weighed, the result giving an approxi- 
mate value of the quantity of mineral salts. If the ash is heavily impreg- 
nated with resistant carbon it can be leached with dilute acetic acid, the 
solution filtered, evaporated, and the filter paper and carbon returned 
to the dish and the whole burned a second time. 



GENERAL METHODS 7 

SUGAR 

Sucrose or cane sugar enters into the composition of a large variety 
of medicinal substances, including elixirs, wines, syrups, cordials, pills, 
tablets, lozenges, pastilles, granular preparations and some powders. 
Lactose or milk sugar occurs in powders. Honey is often used. Com- 
mercial glucose is present in pill and tablet mixtures and to some extent 
probably in liquid preparations. Invert sugar will be present to some 
extent where sucrose has been hydrolyzed by acid. True glucose as a 
decomposition product of glucosides, as well as other less common sugars 
from the same sources will be found. The analyst will be chiefly con- 
cerned with determining the sugar which is present as one of the chief 
bulk ingredients. 

The polariscopic methods for the estimation of sugar may be employed 
in the case of those mixtures which are free from caramel or contain sub- 
stances which are readily removed by lead acetate, and by checking the 
determination by a copper reduction before and after inversion the amount 
can be obtained with a satisfactory degree of accuracy. This quali- 
fication must be made because there are many substances other than 
sugar which will affect the polarization and copper reduction to a greater 
or less extent, and their presence will, of course, have been established 
by a previous qualitative examination. 

Sucrose 1 

Dissolve the normal weight (26 grams) of the substance in water, 
add basic lead acetate carefully, avoiding any excess, then 1-2 mils of alu- 
mina cream, shake, and dilute to 100 mils, filter, rejecting the first 
20 mils of the filtrate, cover the filter with a watch glass and, when suffi- 
cient filtrate is collected, polarize in a 200-mm. tube. The reading so 
obtained is the direct reading (P of formula given below) or polarization 
before inversion. For the invert reading, remove the lead from the solu- 
tion either (1) by adding anhydrous potassium oxalate, a little at a time, 
to the remaining solution, avoiding an excess and removing the precipi- 
tated lead by filtration; or, (2) by adding anhydrous sodium carbonate 
under the same conditions. Introduce 50 mils of the lead-free filtrate 
into a 100-mil flask (if sodium carbonate was used for removing the lead, 
neutralize carefully the excess of sodium carbonate with a few drops of 
dilute hydrochloric acid) and add 25 mils of water. Then add, little by 
little, while rotating the flask, 5 mils of hydrochloric acid (sp. gr. 1.20). 
Heat the flask after mixing, in a water-bath kept at 70° C. in 2\ to 3 
minutes. Maintain a temperature of as nearly 69° C. as possible for 
7 to 1\ minutes, making the total time of heating ten minutes. Remove 
the flask and cool the contents rapidly to 20° C. and dilute to 100 mils. 

1 By Polarization before and after Inversion with Hydrochloric Acid. — A.O.A.C. 



8 GENERAL METHODS AND CRUDE DRUG ASSAYS 

Polarize this solution in a tube provided with a lateral branch and a water 
jacket, maintaining a temperature of 20° C. . This reading must be multi- 
plied by 2 to obtain the invert reading. If it is necessary to work at a 
temperature other than 20° C, which is allowable within narrow limits, 
the volumes must be completed and both direct and invert polariza- 
tions must be made at exactly the same temperature. 

The inversion may also be accomplished as follows: (1) To 50 mils 
of the clarified solution, freed from lead, add 5 mils of hydrochloric acid 
(sp. gr. 1.20) and set aside for twenty-four hours at a temperature not 
below 20° C; or, (2) if the temperature be above 25° C. set aside for 
ten hours. Make up to 100 mils at 20° C. and polarize as directed above. 

Calculate sucrose by one of the following formulas: 

For Substances in which the Invert Solution Contains more than 12 Grams 
of Invert Sugar per 100 Mils. — The following formula is to be used when 
substances like raw sugars are polarized: 

5 _ 100 (P-I) 

T 

142.66-^ 

-j 

in which 

S = per cent of sucrose ; 

P = direct reading normal solution ; 

I = invert reading normal solution ; 

T = temperature at which readings are made. 

For Substances in which the Concentration of the Invert Solution is Less 
than 12 Grams per 100 Mils. — The following formula, which takes into 
account the concentration of the sugar in solution, should be used in all 
other cases. 

s= 100 (P=I) . 

142.66 = ^ = 0.0065(142. 66 = ^= (P=I)) 

in which 

S = per cent of sucrose ; 
P = direct reading normal solution ; 
I = invert reading normal solution; 
T*= temperature. 

TOTAL SUGARS AND SUCROSE BY COPPER REDUCTION 

For the copper reduction, the procedure of Munson and Walker gives 
the greatest satisfaction. The reagents consist of copper sulphate 34.6 
grams to 500 mils; and alkaline tartrate, 173 grams Rochelle Salts, and 
50 grams sodium hydrate to 500 mils. A determination should be made 
on the sample directly, then the amount given by inversion ascertained, 



GENERAL METHODS 9 

and from the figures the amount due to sucrose may be calculated. The 
quantity of the sample to be taken cannot be stated by any hard-and- 
fast rule, and the worker should make a few prehminary tests before 
running the actual determination. For liquids 10 to 25 mils will be suf- 
ficient, and for solids 10 grams will usually suffice. 

After the sample has been accurately measured or weighed, it is intro- 
duced into a 100-mil graduated flask, diluted with water, precipitated 
with an excess of neutral lead acetate and made up to volume. A 25-mil 
aliquot is then precipitated with potassium oxalate, diluted to a definite 
volume without filtering, and the reducing sugars determined in a small 
portion of the clear liquid. Tenmils, or a sufficient quantity of this diluted 
solution are measured out with a pipette or burette and added to a mix- 
ture of 25 mils each of the copper and tartrate solution in a 400-mil 
beaker, 40 mils of water are added, the mixture brought to a boil as rapidly 
as possible, and boiled for two minutes. The cuprous oxide is then fil- 
tered onto an asbestos felt in a porcelain Gooch crucible, using suction, 
washed with warm water, dried with alcohol and ether, placed in an oven 
at 100° C. for half an hour and then cooled and weighed. For the sucrose 
determination a 50-mil aliquot of the original 100-mil solution of the 
sample is precipitated with potassium oxalate, filtered and a 25-mil portion 
of the filtrate inverted with hydrochloric acid as directed under "Sucrose" 
This liquid is then made up to volume and the total reduction determined. 

The number of milligrams of copper reduced by a given amount of 
sugar differs when sucrose is present and when it is absent. In the sugar 
table there are two columns, one for a mixture of invert sugar and sucrose 
in the case of about .4 gram total sugar and another in case of about 2 
grams; in addition there is a column for invert sugar alone. 

The factor for sucrose is 0.95. 

As has been stated above, there are a number of substances other 
than the well-known reducing sugars which throw out cuprous oxide from 
an alkaline copper solution, and for the benefit of the worker the follow- 
ing list has been compiled. It includes most of the individuals with 
which the worker will meet. 

Acetaldehyde and all other aldehydes of the acetic series. 

Arabinose Gallotannic acid Mannitose 

Arsenous acid Glycosuric acid Pectinose 

Chloral Glycuronic acid Pyrogalhc acid 

Chloroform Glycyrrhizin Resorcinol 

Dextrose Iso-dulcite Rhamnose 

Eucalyptose Lactose Sorbinose 

Formaldehyde Levulose Trichlor acetic acid 

Formic acid Maltose Zylose 
Galactose 



10 



GENERAL METHODS AND CRUDE DRUG ASSAYS 



MUNSON AND WALKER'S TABLE 
For calculating dextrose, invert sugar alone, invert sugar in the presence of sucrose 
(0.4 gram and 2 grams total sugar), lactose (two forms), and maltose (anhydrous 
and crystallized). 

[Expressed in milligrams.] 



o 




o> 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


q 


3 

o 




tn 
O 
o 

3 
















3 














o 






3 


u 


"3 

c 


15 




c 




c 


7° 


6 


3 


3 


3 
GO 


H 


o 




w 




w 


C 


CD 

3 
O 


(4 


m 

o 

t-c 


8 u 


CO -_ 
S =3 
e3 M 


1 


q 


6 

S3 


1 


GO 

3 
O 


ft 

3 


ft 

ft 
o 


0) 


> 

C 


O 3 


2 3 
CJOQ 


ffl 


£ 


W 


w 


ft 

3 


o 


o 


Q 


© 


03 


i 


6 


6 


6 


o 


10 


8.9 


4.0 


4.5 


1.6 




3.8 


4.0 


5.9 


6.2 


10 


11 


9.8 


4.5 


5.0 


2.1 




4.5 


4.7 


6.7 


7.0 


11 


12 


10.7 


4.9 


5.4 


2 5 




5.1 


5.4 


7.5 


7.9 


12 


13 


11.5 


5.3 


5.8 


3.0 




5.8 


6.1 


8.3 


8.7 


13 


14 


12.4 


5.7 


6.3 


3.4 




6.4 


6.8 


9.1 


9.5 


14 


15 


13.3 


6.2 


6.7 


3.9 




7.! 


7.5 


9.9 


10.4 


15 


16 


14.2 


6.6 


7.2 


4.3 




7.8 


8.2 


10.6 


11.2 


16 


17 


15.1 


7.0 


7.6 


4 8 




8.4 


8.9 


11.4 


12.0 


17 


18 


16.0 


7.5 


8.1 


5.2 




9 1 


9.5 


12.2 


12.9 


18 


19 


16.9 


7.9 


8.5 


5.7 




9.7 


10.2 


13.0 


13.7 


19 


20 


17.8 


8.3 


8.9 


6.1 




10.4 


10.9 


13.8 


14.6 


20 


• 21 


18.7 


8.7 


9.4 


6.6 




11.0 


11.6 


14.6 


15.4 


21 


22 


19.5 


9.2 


9.8 


7.0 




11.7 


12.3 


15.4 


16.2 


22 


23 


20.4 


9.6 


10.3 


7.5 




12.3 


13.0 


16.2 


17.1 


23 


24 


21.3 


10.0 


10.7 


7.9 




13.0 


13.7 


17.0 


17.9 


24 


25 


22.2 


10.5 


11.2 


8.4 




13.7 


14.4 


17.8 


18.7 


25 


26 


23.1 


10.9 


11.6 


8.8 




14.3 


15.1 


18.6 


19.6 


26 


27 


24.0 


11.3 


12.0 


9.3 




15.0 


15.8 


19.4 


20.4 


27 


28 


24.9 


11.8 


12.5 


9.7 




15.6 


16.5 


20.2 


21.2 


28 


29 


25.8 


12.2 


12.9 


10.2 




16.3 


17.1 


21.0 


22.1 


29 


30 


26.6 


12.6 


13.4 


10.7 


4.3 


16.9 


17.8 


21.8 


22.9 


30 


31 


27.5 


13.1 


.13.8 


11.1 


4.7 


17.6 


18.5 


22.6 


23.7 


31 


32 


28.4 


13.5 


14.3 


11.6 


5 2 


18.3 


19.2 


23.3 


24.6 


32 


33 


29.3 


13.9 


14.7 


12.0 


5.6 


18.9 


19.9 


24.1 


25.4 


33 


34 


30.2 


14.3 


15.2 


12.5 


6.1 


19.6 


20.6 


24.9 


26.2 


34 


35 


31.1 


14.8 


15.6 


12.9 


6.5 


20.2 


21.3 


25.7 


27.1 


35 


36 


32.0 


15.2 


16.1 


13.4 


7.0 


20.9 


22 


26.5 


27.9 


36 


37 


32.9 


15.6 


16.5 


13.8 


7.4 


21.5 


22.7 


27.3 


28.7 


37 


38 


33.8 


16.1 


16.9 


14.3 


7.9 


22.2 


23.4 


28.1 


29.6 


38 


39 


34.6 


16.5 


17.4 


14.7 


8.4 


22.8 


24.1 


28.9 


30.4 


39 


40 


35.5 


16.9 


17.8 


15.2 


8.8 


23.5 


24.8 


29.7 


31.3 


40 


41 


36.4 


17.4 


18.3 


15.6 


9.3 


24.2 


25.4 


30.5 


32.1 


41 


42 


37.3 


17.8 


18.7 


16.1 


9.7 


24.8 


26.1 


31.3 


32.9 


42 


43 


38.2 


18.2 


19.2 


16.6 


10.2 


25.5 


26.8 


32.1 


33.8 


43 


44 


39.1 


18.7 


19.6 


17.0 


10.7 


26.1 


27.5 


32.9 


34.6 


44 


45 


40.0 


19.1 


20.1 


17.5 


11.1 


26.8 


28.2 


33.7 


35.4 


45 


46 


40.9 


19.6 


20.5 


17.9 


11.6 


27.4 


28.9 


34.4 


36.3 


46 


47 


41.7 


20.0 


21.0 


18.4 


12.0 


28.1 


29.6 


35.2 


37.1 


47 


48 


42.6 


20.4 


21.4 


18.8 


12.5 


28.7 


30.3 


36.0 


37.9 


48 


49 


43.5 


20.9 


21.9 


19.3 


12.9 


29.4 


31.0 


36.8 


38.8 


49 


50 


44.4 


21.3 


22.3 


19.7 


13.4 


30.1 


31.7 


37.6 


39.6 


50 


51 


45.3 


21.7 


22.8 


20.2 


13.9 


30.7 


32.4 


38.4 


40.4 


51 


52 


46.2 


22.2 


23.2 


20.7 


14.3 


31.4 


33.0 


39.2 


41.3 


52 


53 


47.1 


22.6 


23.7 


21.1 


14.8 


32.1 


33.7 


40.0 


42.1 


53 


54 


48.0 


23.0 


24.1 


21.6 


15.2 


32.7 


34.4 


40.8 


42.9 


54 


55 


48.9 


23.5 


24.6 


22.0 


15.7 


33.4 


35.1 


41.6 


43.8 


55 


56 


49.7 


23.9 


25.0 


22.5 


16.2 


34.0 


35.8 


42.4 


44.6 


56 


57 


50.6 


24.3 


25.5 


22.9 


16.6 


34.7 


36.5 


43.2 


45.4 


57 


58 


51.5 


24.8 


25.9 


23.4 


17.1 


35.4 


37.2 


44.0 


46.3 


58 


59 


52.4 


25.2 


26.4 


23.9 


17.5 


36.0 


37.9 


44.8 


47.1 


59 


60 


53.3 


25.6 


26.8 


24. ?! 


18.0 


36.7 


38.6 


45.6 


48.0 


60 


61 


54.2 


26.1 


27.3 


24. 8 


18.5 


37.3 


39.3 


46.3 


48.8 


61 


62 


55. 1 


26.5 


27.7 


25,2 


18 9 


38.0 


40.0 


47.1 


49.6 


62 


63 


56.0 


27.0 


28.2 


25.7 


1 19 4 


38.6 


40.7 


47.9 


50.5 


63 


64 


56.8 


27.4 


28.6 


26.2 


1 19.8 


39.3 


41.4 


48 7 


51.3 


64 



GENERAL METHODS 



11 



MUNSON AND WALKER'S TABLE— Continued 

[Expressed in milligrams.] 



§ 




« 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


O 


3 




o 
















3 


o 




o 
















o 


<x> 




J3 




"eS 


_ 










45 


'3 

o 


3 


2, 


M 
3 
W 


O 


c3 
O 




O 




3 


'3 

O 


5 


u 


a 


c3 c3 


S «4 


6 


o 


6 


O 


m 

3 


o 


<D 


2 




r K M 


C3 M 


a 




3 


SJ 


O 


a 

3 


a 
o 


o 


05 

> 

a 


O 3 


2 3 
000 


W 


1 


w 


E 


a 


o 


O 


Q 


© 


iM 


6 


6 


6 


6 


O 


65 


57.7 


27.8 


29.1 


26.6 


20.3 


40.0 


42.1 


49.5 


52.1 


65 


66 


. 58.6 


28.3 


29.5 


27.1 


20.8 


40.6 


42.8 


50.3 


53.0 


66 


67 


59.5 


28.7 


30.1 


27.5 


21.2 


41.3 


43.5 


51.1 


53.8 


67 


68 


60.4 


29.2 


30.4 


28.0 


21.7 


41.9 


44.2 


51.9 


54.6 


68 


69 


61.3 


29.6 


30.9 


28.5 


22.2 


42.6 


44.8 


52.7 


55.5 


69 


70 


62.2 


30.0 


31.3 


28.9 


22.6 


43.3 


45.5 


53.5 


56.3 


70 


71 


63.1 


30.5 


31.8 


29.4 


23.1 


43.9 


46.2 


54.3 


57.1 


71 


72 


64.0 


30.9 


32.3 


29.8 


23.5 


44.6 


46.9 


55.1 


58.0 


72 


73 


64.8 


31.4 


32.7 


30.3 


24.0 


45.2 


47.6 


55.9 


58.8 


73 


74 


65.7 


31.8 


33.2 


30.8 


24.5 


45.9 


48.3 


56.7 


59.6 


74 


75 


66 6 


32.2 


33.6 


31.2 


24.9 


46.6 


49.0 


57.5 


60.5 


75 


76 


67.5 


32.7 


34.1 


31.7 


25.4 


47.2 


49.7 


58.2 


61.3 


76 


77 


68.4 


33.1 


34.5 


32.1 


25.9 


47.9 


50.4 


59.0 


62.1 


77 


78 


69.3 


33.6 


35.0 


32.6 


26.3 


48.5 


51.1 


59.8 


63.0 


78 


79 


70.2 


34.0 


35.4 


33.1 


26.8 


49.2 


51.8 


60.6 


63.8 


79 


80 


71.1 


34.4 


35.9 


33.5 


27.3 


49.9 


52.5 


61.4 


64.6 


80 


81 


71.9 


34.9 


36.3 


34.0 


27.7 


50.5 


53.2 


62.2 


65.5 


81 


82 


72.8 


35.3 


36.8 


34.5 


28.2 


51.2 


53.9 


63.0 


66.3 


82 


83 


73.7 


35.8 


37.3 


34.9 


28.6 


51.8 


54.6 


63.8 


67 1 


83 


84 


74.6 


36.2 


37.7 


35.4 


29.1 


52.5 


55.3 


64,6 


68.0 


84 


85 


75.5 


36.7 


38.2 


35.8 


29.6 


53.1 


56.0 


65.4 


68.8 


85 


86 


76.4 


37.1 


38.6 


36.3 


30.0 


53.8 


56.6 


66.2 


69.7 


86 


87 


77.3 


37.5 


39.1 


36.8 


30.5 


54.5 


57 3 


67.0 


70.5 


87 


88 


78.2 


38.0 


39.5 


37.2 


31.0 


55.1 


58.0 


67.8 


71.3 


88 


89 


79.1 


38.4 


40.0 


37.7 


31.4 


55.8 


58.7 


68.5 


72.2 


89 


90 


79.9 


38.9 


40.4 


38.2 


31.9 


56.4 


59.4 


69.3 


73.0 


90 


91 


80.8 


39.3 


40.9 


38.6 


32.4 


57.1 


60.1 


70.1 


73.8 


91 


92 


81.7 


39.8 


41.4 


39.1 


32.8 


57.8 


60.8 


70 9 


74.7 


92 


93 


82.6 


40.2 


41.8 


39.6 


33.3 


58.4 


61.5 


71.7 


75.5 


93 


94 


83.5 


40.6 


42.3 


40.0 


33.8 


59.1 


62.2 


72.5 


76.3 


94 


95 


84.4 


41.1 


42.7 


40.5 


34.2 


59.7 


62.9 


73.3 


77.2 


95 


96 


85.3 


41.5 


43.2 


41.0 


34.7 


60.4 


63.6 


74.1 


78.0 


96 


97 


86.2 


42.0 


43.7 


41.4 


35.2 


61.1 


64.3 


74.9 


78.8 


97 


98 


87.1 


42.4 


44.1 


41.9 


35.6 


61.7 


65.0 


75.7 


79.7 


98 


99 


87.9 


42.9 


44.6 


42.4 


36.1 


62.4 


65.7 


76.5 


80.5 


99 


100 


88.8 


43.3 


45.0 


42.8 


36.6 


63.0 


66.4 


77.3 


81.3 


100 


101 


89.7 


43.8 


45.5 


43.3 


37.0 


63.7 


67.1 


78.1 


82.2 


101 


102 


90.6 


44.2 


46.0 


43.8 


37.5 


64.4 


67.8 


78.8 


83.0 


102 


103 


91.5 


44.7 


46.4 


44.2 


38.0 


65.0 


68.5 


79.6 


83.8 


103 


104 


92.4 


45.1 


46.9 


44.7 


38.5 


65.7 


69.1 


80.4 


84.7 


104 


105 


93.3 


45.5 


47.3 V 


45.2 


38.9 


66.4 


69.8 


81.2 


85.5 


105 


106 


94.2 


46.0 


47.8 


45.6 


39.4 


67.0 


70.5 


82.0 


86.3 


106 


107 


95.0 


46.4 


48.3 


46.1 


39.9 


67.7 


71.2 


82.8 


87.2 


107 


108 


95.9 


46.9 


48.7 


46.6 


40.3 


68.3 


71.9 


83.6 


88.0 


108 


109 


96.8 


47.3 


49.2 


47.0 


40.8 


69.0 


72.6 


84.4 


88.8 


109 


110 


97.7 


47.8 


49.6 


47.5 


41.3 


69.7 


73.3 


85.2 


89.7 


110 


111 


98.6 


48.2 


50.1 


48.0 


41.7 


70.3 


74 


86 


90.5 


111 


112 


99.5 


48.7 


50.6 


48.4 


42.2 


71.0 


74 7 


86.8 


91.3 


112 


113 


100.4 


49.1 


51.0 


48.9 


42.7 


•71.6 


75.4 


87.6 


92.2 


113 


114 


101 . 3 


49.6 


51.5 


49.4 


43.2 


72.3 


76.1 


88.4 


93.0 


114 


115 


102.2 


50.0 


51.9 


49.8 


43.6 


73.0 


76.8 


89.2 


93.9 


115 


116 


103.0 


50.5 


52.4 


50.3 


44.1 


73.6 


77.5 


90.0 


94.7 


116 


117 


103.9 


50.9 


52.9 


50.8 


44.6 


74.3 


78.2 


90.7 


95.5 


117 


118 


104.8 


51.4 


53.3 


51.2 


45.0 


75.0 


78.9 


91.5 


96.4 


118 


119 


105.7 


51.8 


53.8 


51.7 


45.5 


75.6 


79.6 


92.3. 


97.2 


119 



12 



GENERAL METHODS AND CRUDE DRUG ASSAYS 



MUNSON AND WALKER'S TABLE— Continued 

[Expressed in milligrams.] 



6 




'S' 




Invert Sugar 
and Sucrose 


Lactose 


Mal 


rosE 


6 


B 






o 
















3 


O 














o 






9 


u 


"3 
"o 


"s3 




O 




O 


12 


o 


o 


2- 


c3 
3 


H 


o 




W 




ffi 


O 


3 




to 
O 


m 


e8 rt 


£ =3 


d 


6 


d 


d 


3 


o 


CD 






r * M 


c3 M 




g 


s 


a 


O 


ft 

3 


a 
o 




> 

(3 


O 3 
«8Q 


2 3 


K 


w 


W 


W 


ft 

3 


o 


D 


Q 




© 


<N 


o 


d 


d 


d 


o 


120 


106.6 


52.3 


54.3 


52.2 


46.0 


76.3 


80.3 


93.1 


98.0 


120 


121 


107.5 


52.7 


54.7 


52.7 


46.5 


76.9 


81.0 


93.9 


98.9 


121 


122 


108.4 


53.2 


55.2 


53.1 


46.9 


77.6 


81.7 


94.7 


99.7 


122 


123 


109.3 


53.6 


55.7 


53.6 


47.4 


78.3 


82.4 


95.5 


100.5 


123 


124 


110.1 


54.1 


56.1 


54.1 


47.9 


78.9 


83.1 


96.3 


101.4 


124 


125 


111.0 


54.5 


56.6 


54.5 


48.3 


79.6 


83.8 


97.1 


102.2 


125 


126 


111.9 


55.0 


57.0 


55.0 


48.8 


80.3 


84.5 


97.9 


103.0 


126 


127 


112.8 


55.4 


57.5 


55.5 


49.3 


80.9 


85.2 


98.7 


103.9 


127 


128 


113.7 


55 9 


58.0 


55.9 


49.8 


81.6 


85.9 


99.4 


104.7 


128 


129 


114.6 


56.3 


58.4 


56.4 


50.2 


82.2 


86.6 


100.2 


105.5 


129 


130 


115.5 


56.8 


58.9 


56.9 


50.7 


82.9 


87.3 


101.0 


106.4 


130 


131 


116.4 


57.2 


59.4 


57.4 


51.2 


83.6 


88.0 


101.8 


107.2 


131 


132 


117.3 


57.7 


59.8 


57.8 


51.7 


84.2 


88.7 


102.6 


108.0 


132 


133 


118.1 


58.1 


60.3 


58.3 


52.1 


84.9 


89.4 


103.4 


108.9 


133 


134 


119.0 


58.6 


60.8 


58.8 


52.6 


85.5 


90.1 


104.2 


109.7 


134 


135 


119.9 


59.0 


61.2 


59.3 


53.1 


86.2 


90.8 


105.0 


110.5 


135 


136 


120.8 


59.5 


61.7 


59.7 


53.6 


86.9 


91.5 


105.8 


111.4 


136 


137 


121.7 


60.0 


62.2 


60.2 


54.0 


87.5 


92.1 


106.6 


112.2 


137 


138 


122.6 


60.4 


62.6 


60.7 


54.5 


88.2 


92.8 


107.4 


113.0 


138 


139 


123.5 


60.9 


63.1 


61.2 


55.0 


88.9 


93.5 


108.2 


113.9 


139 


140 


124.4 


61.3 


63.6 


61.6 


55.5 


89.5 


94.2 


109.0 


114.7 


140 


141 


125.2 


61.8 


64.0 


62.1 


55.9 


90.2 


94.9 


109.8 


115.5 


141 


142 


126.1 


62.2 


64.5 


62.6 


56.4 


90.8 


95.6 


110.5 


116.4 


142 


143 


127.0 


62.7 


65.0 


63.1 


56.9 


91.5 


96.3 


111.3 


117.2 


143 


144 


127.9 


63.1 


65.4 


63.5 


57.4 


92.2 


97.0 


112.1 


118.0 


144 


145 


128 8 


63.6 


65.9 


64.0 


57.8 


92.8 


97.7 


112.9 


118.9 


145 


146 


129.7 


64.0 


66.4 


64.5 


58.3 


93.5 


98.4 


113.7 


119.7 


146 


147 


130.6 


64.5 


66.9 


65.0 


58.8 


94.2 


99.1 


114.5 


120.5 


147 


148 


131 5 


65.0 


67.3 


65.4 


59.3 


94.8 


99.8 


115.3 


121.4 


148 


149 


132.4 


65.4 


67.8 


65.9 


59.7 


95.5 


100.5 


116.1 


122.2 


149 


150 


133.2 


65.9 


68.3 


66.4 


60.2 


96.1 


101.2 


116.9 


123.0 


150 


151 


134.1 


66.3 


68.7 


66.9 


60.7 


96.8 


101.9 


117.7 


123.9 


151 


152 


135.0 


66.8 


69.2 


67.3 


61.2 


97.5 


102.6 


118.5 


124.7 


152 


153 


135.9 


67.2 


69.7 


67.8 


61.7 


98.1 


103.3 


119.3 


125.5 


153 


154 


136.8 


67.7 


70.1 


68.3 


62.1 


98.8 


104.0 


120.0 


126.4 


154 


155 


137.7 


68.2 


70.6 


68.8 


62.6 


99.5 


104.7 


120.8 


127.2 


155 


156 


138.6 


68.6 


71.1 


69.2 


63.1 


100.1 


105.4 


121.6 


128.0 


156 


157 


139.5 


69.1 


71.6 


69.7 


63.6 


100.8 


106.1 


122.4 


128.9 


157 


158 


140.3 


69.5 


72.0 


70.2 


64.1 


101.5 


106.8 


123.2 


129.7 


158 


159 


141.2 


70.0 


72.5 


70.7 


64.5 


102.1 


107.5 


124.0 


130.5 


159 


160 


142.1 


70.4 


73.0 


71.2 


65.0 


102.8 


108.2 


124.8 


131.4 


160 


161 


143.0 


70.9 


73.4 


71.6 


65.5 


103.4 


108.9 


125.6 


132.2 


161 


162 


143.9 


71.4 


73.9 


72.1 


66.0 


104.1 


109.6 


126.4 


133.0 


162 


163 


144.8 


71.8 


74.4 


72.6 


66.5 


104.8 


110.3 


127.2 


133.9 


163 


164 


145.7 


72.3 


74.9 


73.1 


66.9 


105.4 


111.0 


128.0 


134.7 


164 


165 


146.6 


72.8 


75.3 


73.6 


67.4 


106.1 


111.7 


128.8 


135.5 


165 


166 


147.5 


73.2 


75.8 


74.0 


67.9 


-06.8 


112.4 


129.6 


136.4 


166 


167 


148.3 


73.7 


76.3 


74.5 


68.4 


107.4 


113.1 


130.3 


137.2 


167 


168 


149.2 


74.1 


76.8 


75.0 


68.9 


108.1 


113.8 


131.1 


138.0 


168 


169 


150.1 


74.6 


77.2 


75.5 


69.3 


108.8 


114.5 


131.9 


138.9 


169 


170 


151.0 


75.1 


77.7 


76.0 


69.8 


109.4 


115.2 


132.7 


139.7 


170 


171 


151.9 


75.5 


78.2 


76.4 


70.3 


110.1 


115.9 


133.5 


140.5 


161 


172 


152.8 


76.0 


78.7 


76.9 


70.8 


111.8 


116.6 


134.3 


141.4 


172 


173 


153.7 


76.4 


79.1 


77.4 


71.3 


111.4 


117.3 


135.1 


142.2 


173 


174 


154.6 


. 76.9 


79.6 


77.9 


71.7 


112.1 


118.0 


1-35.9 


143.0 


174 



GENERAL METHODS 



13 



MUNSON AND WALKER'S TABLE— Continued 

[Expressed in milligrams.] 



f 




« 
o 

3 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


3 


O 














o 






3 


u 


"3 
o 


"* 




q 




Q 


32 


"x 
O 


3 


T3 


33 

M 

3 


H 


o 
H 








E 


O 


m 

3 

o 


It 

o 


m 

O 


m 


=3 03 


GO ., 

S3 H) 


1 


o 


1 


6 


to 

3 
O 


I 


a 
P. 
o 


0> 


3 
> 

c. 


O 3 


2 3 


tg 


^ 


W 


K 


a 

3 


O 


Q 


Q 


© 


<N 


6 


3 


6 


6 


o 


175 


155.5 


77.4 


80.1 


78.4 


72.2 


112.8 


118.7 


136.7 


143.9 


175 


176 


156.3 


77.8 


80.6 


78.8 


72.7 


113.4 


119.4 


137.5 


144.7 


176 


177 


157.2 


78.3 


81.0 


79.3 


73.2 


114.1 


120.1 


138.3 


145.5 


177 


178 


158.1 


78.8 


81.5 


79.8 


73.7 


114.8 


120.8 


139.1 


146.4 


178 


179 


159.0 


79.2 


82.0 


80.3 


74.2 


115.4 


121.5 


139.8 


147.2 


179 


180 


159.9 


79.7 


82.5 


80.8 


74.6 


116.1 


122.2 


140.6 


148.0 


180 


181 


160.8 


80.1 


82.9 


81.3 


75.1 


116.7 


122.9 


141.4 


148.9 


181 


182 


161.7 


80.6 


83.4 


81.7 


75.6 


117.4 


123.6 


142.2 


149.7 


182 


183 


162.6 


81.1 


83.9 


82.2 


76.1 


118.1 


124.3 


143.0 


150.5 


183 


184 


163.4 


81.5 


84.4 


82.7 


76.6 


118.7 


125.0 


143.8 


151.4 


184 


185 


164.3 


82.0 


84.9 


83.2 


77.1 


119.4 


125.7 


144.6 


152.2 


185 


186 


165.2 


82.5 


85.3 


83.7 


77.6 


120.1 


126.4 


145.4 


153.0 


186 


187 


166.1 


82.9 


85.8 


84.2 


78.0 


120.7 


127.1 


146.2 


153.9 


187 


188 


167.0 


83.4 


86.3 


84.6 


78.5 


121.4 


127.8 


147.0 


154.7 


188 


189 


167.9 


83.9 


86.8 


85.1 


79.0 


122.1 


128.5 


147.8 


155.5 


189 


190 


168.8 


84.3 


87.2 


85.6 


79.5 


122.7 


129.2 


148.6 


156.4 


190 


191 


169.7 


84.8 


87.7 


86.1 


80.0 


123.4 


129.9 


149.3 


157.2 


191 


192 


170.5 


85.3 


88.2 


86.6 


80.5 


124.1 


130.6 


150.1 


158.0 


192 


193 


171.4 


85.7 


88.7 


87.1 


81.0 


125.7 


131.3 


150.9 


158.9 


193 


194 


172.3 


86.2 


89.2 


87.6 


81.4 


125.4 


132.0 


151.7 


159.7 


194 


195 


173.2 


86.7 


89.6 


88.0 


81.9 


126.1 


132.7 


152.5 


160.5 


195 


196 


174.1 


87.1 


90.1 


88.5 


82.4 


126.7 


133.4 


153.3 


161.4 


196 


197 


175.0 


87.6 


90.6 


89.0 


82.9 


127.4 


134.1 


154.1 


162.2 


197 


198 


175.9 


88.1 


91.1 


89.5 


83.4 


128.1 


134.8 


1.54.9 


163.0 


198 


199 


176.8 


88.5 


91.6 


90.0 


83.9 


128.7 


135.5 


155.7 


163.9 


199 


200 


177.7 


89.0 


92.0 


90.5 


84.4 


129.4 


136.2 


156.5 


164.7 


200 


201 


178.5 


89.5 


92.5 


91.0 


84.8 


130.0 


136.9 


157.3 


165.5 


201 


202 


179.4 


89.9 


93.0 


91.4 


85.3 


130.7 


137.6 


158.1 


166.4 


202 


203 


180.3 


90.4 


93.5 


91.9 


85.8 


131.4 


138.3 


158.8 


167.2 


203 


204 


181.2 


90.9 


94.0 


92.4 


86.3 


132.0 


139.0 


159.6 


168.0 


204 


205 


182.1 


91.4 


94.5 


92.9 


86.8 


132.7 


139.7 


160.4 


168.9 


205 


206 


183.0 


91.8 


94.9 


93.4 


87.3 


133.4 


140.4 


161.2 


169.7 


206 


207 


183.9 


92.3 


95.4 


93.9 


87.8 


134.0 


141.1 


162.0 


170.5 


207 


208 


184.8 


92.8 


95.9 


94.4 


88.3 


134.7 


141.8 


162.8 


171.4 


208 


209 


185.6 


93.2 


96.4 


94.9 


88.8 


135.4 


142.5 


163.6 


172.2 


209 


210 


186.5 


93.7 


96.9 


95.4 


89.2 


136.0 


143.2 


164.4 


173.0 


210 


211 


187.4 


94.2 


97.4 


95.8 


89.7 


136.7 


143.9 


165.2 


173.8 


211 


212 


188.3 


94.6 


97.8 


96.3 


90.2 


137.4 


144.6 


166.0 


174.7 


212 


213 


189.2 


95.1 


98.3 


96.8 


90.7 


138.0 


145.3 


166.8 


175.5 


213 


214 


190.1 


95.6 


98.8 


97.3 


91.2 


138.7 


146.0 


167.5 


176.4 


214 


215 


191.0 


96.1 


99.3 


97.8 


91.7 


139.4 


146.7 


168.3 


177.2 


215 


216 


191.9 


96.5 


99.8 


98.3 


92.2 


140.0 


147.4 


169.1 


178.0 


216 


217 


192.8 


97.0 


100.3 


98.8 


92.7 


140.7 


148.1 


169.9 


178.9 


217 


218 


193.6 


97.5 


100.8 


99.3 


93.2 


141.4 


148.8 


170.7 


179.7 


218 


219 


194.5 


98.0 


101.2 


99.8 


93.7 


142.0 


149.5 


171.5 


180 5 


219 


220 


195.4 


98.4 


101.7 


100.3 


94.2 


142.7 


150.2 


172.3 


181.4 


220 


221 


196.3 


98.9 


102.2 


100.8 


94.7 


143.4 


150.9 


173.1 


182.2 


221 


222 


197.2 


99.4 


102.7 


101.2 


95.1 


144.0 


151.6 


173 9 


183.0 


222 


223 


198.1 


99.9 


103.2 


101.7 


95.6 


144.7 


152 3 


174.7 


183.9 


223 


224 


199.0 


100.3 


103.7 


102.2 


96.1 


145.4 


153.0 


175.5 


184.7 


224 


225 


199.9 


100.8 


104.2 


102.7 


96.6 


146.0 


153.7 


176.2 


185.5 


225 


226 


200.7 


101.3 


104.6 


103.2 


97.1 


146.7 


154.4 


177.0 


186.4 


226 


227 


201.6 


101.8 


105.1 


103.7 


97.6 


147.4 


155.1 


177.8 


187 2 


227 


228 


202.5 


102.2 


106.6 


104.2 


98.1 


148.0 


155.8 


178.6 


188.0 


228 


229 


203.4 


102.7 


106.1 


104.7 


98.6 


148.7 


156.5 


179.4 


188 8 


229 



14 



GENERAL METHODS AND CRUDE DRUG ASSAYS 



MUNSON AND WALKERS TABLE— Continued 

[Expressed in milligrams.] 



I 




§ 
E 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


3 


o 














o 






H 


















OP 

!2 




5 


u 


Is 

o 


*3 




O 




o 




'3 

o 


3 

o 


3 


a 


H 


o 




w 






O 


CO 

o 


u 


u 






2 u 
c3 w> 


i 


i 


1 


6 

SJ 


so 

3 
O 


(4 
ft 

3 


ft 
ft 
o 


X 


0> 

> 
1 


■ O 3 


u 3 


K 


X 


X 


K 


u 

a 

3 


o 


Q 


Q 


6 


CM 


6 


6 


6 


3 


u 


230 


204.3 


103.2 


106.6 


105.2 


99.1 


149.4 


157.2 


180.2 


189.7 


230 


231 


205.2 


103.7 


107.1 


105.7 


99.6 


150.0 


157.9 


181.0 


190.5 


231 


232 


206.1 


104.1 


107.6 


106.2 


100.1 


150.7 


158.6 


181.8 


191.3 


232 


233 


207.0 


104.6 


108.1 


106.7 


100.6 


151.4 


159.3 


182.6 


192.2 


233 


234 


207.9 


105.1 


108.6 


107.2 


101.1 


152.0 


160.0 


183.4 


193.0 


234 


235 


208.7 


105.6 


109.1 


107.7 


101.6 


152.7 


160.7 


184.2 


193.8 


235 


236 


209.6 


106.0 


109.5 


108.2 


102.1 


153.4 


161.4 


184.9 


194.7 


236 


237 


210.5 


106.5 


110.0 


108.7 


102.6 


154.0 


162.1 


185.7 


195.5 


237 


238 


211.4 


107.0 


110.5 


109.2 


103.1 


154.7 


162.8 


186.5 


196.3 


238 


239 


212.3 


107.5 


111.0 


109.6 


103.5 


155.4 


163.5 


187.3 


197.2 


239 


240 


213.2 


108.0 


111.5 


110.1 


104.0 


156.1 


164.3 


188.1 


198.0 


240 


241 


214.1 


108.4 


112.0 


110.6 


104.5 


156.7 


165.0 


188.9 


198.8 


241 


242 


215.0 


108.9 


112.5 


111.1 


105.0 


157.4 


165.7 


189.7 


199.7 


242 


243 


215.8 


109.4 


113.0 


111.6 


105.5 


158.1 


166.4 


190.5 


200.5 


243 


244 


216.7 


109.9 


113.5 


112.1 


106.0 


158.7 


167.1 


191.3 


201.3 


244 


245 


217.6 


110.4 


114.0 


112.6 


106.5 


159.4 


167.8 


192.1 


202.2 


245 


246 


218.5 


110.8 


114.5 


113.1 


107.0 


160.1 


168.5 


192.9 


203.0 


246 


247 


219.4 


111.3 


115.0 


113.6 


107.5 


160.7 


169.2 


193.6 


203.8 


247 


248 


220.3 


111.8 


115.4 


114.1 


108.0 


161.4 


169.9 


194.4 


204.7 


248 


249 


221.2 


112.3 


115.9 


114.6 


108.5 


162.1 


170.6 


195.2 


205.5 


249 


250 


222.1 


112.8 


116.4 


115.1 


109.0 


162.7 


171.3 


196.0 


206.3 


250 


251 


223.0 


113.2 


116.9 


115.6 


109.5 


163.4 


172.0 


196.8 


207.2 


251 


252 


223.8 


113.7 


117.4 


116.1 


110.0 


164.1 


172.7 


197.6 


208.0 


252 


253 


224.7 


114.2 


117.9 


116.6 


110.5 


164.7 


173.4 


195.4 


208.8 


253 


254 


225.6 


114.7 


118.4 


117.1 


111.0 


165.4 


174.1 


199.2 


209.7 


254 


255 


226.5 


115.2 


118.9 


117.6 


111.5 


166.1 


174.8 


200.0 


210.5 


255 


256 


227.4 


115.7 


119.4 


118.1 


112.0 


166.8 


175.5 


200.8 


211.3 


256 


257 


228.3 


116.1 


119.9 


118.6 


112.5 


167.4 


176.2 


201.6 


212.2 


257 


258 


229.2 


116.6 


120.4 


119.1 


113.0 


168.1 


176.9 


202.3 


213.0 


258 


259 


230.1 


117.1 


120.9 


119.6 


113.5 


168.8 


177.6 


203.1 


213.8 


259 


260 


231 . 


117.6 


121.4 


120.1 


114.0 


169.4 


178.3 


203.9 


214.7 


260 


261 


231.8 


118.1 


121.9 


120.6 


114.5 


170.1 


179.0 


204.7 


215.5 


261 


262 


232 . 7 


118.6 


122.4 


121.1 


115.0 


170.8 


179.8 


205.5 


216.3 


262 


263 


233.6 


119.0 


122.9 


121.6 


115.5 


171.4 


180.5 


206:3 


217.2 


263 


264 


234 5 


119.5 


123.4 


122.1 


116.0 


172.1 


181.2 


207.1 


218.0 


264 


265 


235 4 


120.0 


123.9 


122.6 


116.5 


172.8 


181.9 


207.9 


218.8 


265 


266 


236.3 


120.5 


124.4 


123.1 


117.0 


173.5 


182.6 


208.7 


219.7 


266 


267 


237.2 


121.0 


124.9 


123.6 


117.5 


174.1 


183.3 


209.5 


220.5 


267 


268 


238.1 


121.5 


125.4 


124.1 


118.0 


174.8 


184.0 


210.3 


221.3 


268 


269 


238.9 


122.0 


125.9 


124.6 


118.5 


175.5 


184.7 


211.0 


222.1 


269 


270 


239.8 


122.5 


126.4 


125.1 


119.0 


175.1 


185.4 


211.8 


223.0 


270 


271 


240.7 


122.9 


126.9 


125.6 


119.5 


176.8 


186.1 


212.6 


223.8 


271 


272 


241.6 


123.4 


127.4 


126.2 


120.0 


177.5 


186.8 


213.4 


224.6 


272 


273 


242.5 


123.9 


127.9 


126.7 


120.6 


178.1 


187.5 


214.2 


225.5 


273 


274 


243.4 


124.4 


128.4 


127.2 


121.1 


178.8 


188.2 


215.0 


226.3 


274 


275 


244.3 


124.9 


128.9 


127.7 


121.6 


179.5 


188.9 


215.8 


227.1 


275 


276 


245.2 


125.4 


129.4 


128.2 


122.1 


180.2 


189.6 


216.6 


228.0 


276 


277 


246.1 


125.9 


129.9 


128.7 


122.6 


180 8 


190.3 


217.4 


228.8 


277 


278 


246.9 


126.4 


130.4 


129.2 


123.1 


181.5 


191.0 


218.2 


229.6 


278 


279 


247.8 


126.9 


130.9 


129.7 


123.6 


182.2 


191.7 


218.9 


230.5 


279 


280 


248.7 


127.3 


131.4 


130.2 


124.1 


182.8 


192.4 


219.7 


231.3 


280 


281 


249.6 


127.8 


131.9 


130.7 


124.6 


183.5 


193.1 


220.5 


232.1 


281 


282 


250.5 


128.3 


132.4 


131.2 


125.1 


184.2 


193.9 


221.3 


233.0 


282 


283 


251 . 4 


128.8 


132.9 


131.7 


125.6 


184.8 


194.6 


222.1 


233.8 


283 


284 


252.3 


129.3 


133.4 


132.2 


126.1 


185.5 


195.3 


222.9 


234.6 


284 



GENERAL METHODS 



15 



MUNSON AND WALKER'S TABLE— Continued 

[Expressed in milligrams.] 



? 




IT 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


6 


3 




o 

3 
















3 


o 














o 


12 




9 


u 


"8 
o 


"8 




O 




O 


12 


o 


"3 
O 


3 


M 

3 


H 


o 
H 




ffi 




w 


O 


m 

§ 




EC 

O 




S 8 

8 M 


| 


1 


6 


o 


3 
O 


u 
ft 

3 


ft 
ft 
o 


0* 


> 

a 


O 3 


2 3 


ffi 


H 


i 


W 


ft 

3 


o 


O 


p 


O* 


<N 


Q~ 


"o 


6 


6 


Q 


285 


253.2 


129.8 


133.9 


132.7 


126.6 


186.2 


196.0 


223.7 


235.5 


285 


280 


254.0 


130.3 


134.4 


133.2 


127.1 


186.9 


196.7 


224.5 


236.3 


286 


287 


254.9 


130.8 


134.9 


133.7 


127.6 


187.5 


197.4 


225.3 


237.1 


287 


288 


255.8 


131.3 


135.4 


134.3 


128.1 


188.2 


198.1 


226.1 


238.0 


288 


289 


256.7 


131.8 


135.9 


134.8 


128.6 


188.9 


198.8 


226.9 


238.8 


289 


290 


257.6 


132.3 


136.4 


135.3 


129.2 


189.5 


199.5 


227.6 


239.6 


290 


291 


258.5 


132.7 


136.9 


135.8 


129.7 


190.2 


200.2 


228.4 


240.5 


291 


292 


259.4 


133.2 


137.4 


136.3 


130.2 


190.9 


200.9 


229 .2 


241.3 


292 


293 


260.3 


133.7 


137.9 


136.8 


130.7 


191.5 


201.6 


230.0 


242.1 


293 


294 


261.2 


134.2 


138.4 


137.3 


131.2 


192.2 


202.3 


230.8 


242.9 


294 


295 


262.0 


134.7 


138.9 


137.8 


131.7 


192.9 


203.0 


231.6 


243.8 


295 


296 


262.9 


135.2 


139.4 


138.3 


132.2 


193.6 


203.7 


232.4 


244.6 


296 


297 


263.8 


135.7 


140.0 


138.8 


132.7 


194.2 


204.4 


233.2 


245.4 


297 


298 


264.7 


136.2 


140.5 


139.4 


133.2 


194.9 


205.1 


234.0 


246.3 


298 


299 


265.6 


136.7 


.141.0 


139.9 


133.7 


195.6 


205.8 


234.8 


247.1 


299 


300 


266.5 


137.2 


141.5 


140.4 


134.2 


196.2 


206.6 


235.5 


247.9 


300 


301 


267.4 


137.7 


142.0 


140.9 


134.8 


196.9 


207.3 


236.3 


248.8 


301 


302 


268.3 


138.2 


142 . 5 


141.4 


135.3 


197.6 


208.0 


237.1 


249.6 


302 


303 


269.1 


138.7 


143.0 


141.9 


135.8 


198.3 


208.7 


237.9 


250.4 


303 


304 


270.0 


139.2 


143.5 


142.4 


136.3 


198.9 


209.4 


238.7 


251.3 


304 


305 


270.9 


139.7 


144.0 


142.9 


136.8 


199.6 


210.1 


239.5 


252.1 


305 


306 


271.8 


140.2 


144.5 


143.4 


137.3 


200.3 


210.8 


240.3 


252.9 


306 


307 


272.7 


140.7 


145.0 


144.0 


137.8 


201.0 


211.5 


241.1 


253.8 


307 


308 


273.6 


141.2 


145.5 


144.5 


138.3 


201.6 


212.2 


241.9 


254.6 


308 


309 


274.5 


141.7 


146.1 


145.0 


138.8 


202.3 


212.9 


242.7 


255.4 


309 


310 


275.4 


142.2 


146.6 


145 . 5 


139.4 


203 . 


213.7 


243.5 


256 . 3 


310 


311 


276.3 


142.7 


147.1 


146.0 


139.9 


203.6 


214.4 


244.2 


257.1 


311 


312 


277.1 


143.2 


147.6 


146.5 


140.4 


204.3 


215.1 


245.0 


257.9 


312 


313 


278.0 


143.7 


148.1 


147.0 


140.9 


205.0 


215.8 


245.8 


258.8 


313 


314 


278.9 


144.2 


148.6 


147.6 


141.4 


205.7 


216.5 


246.6 


259.6 


314 


315 


279.8 


144.7 


149.1 


148.1 


141.9 


206.3 


217.2 


247.4 


260.4 


315 


316 


280.7 


145.2 


149.6 


148.6 


142.4 


207.0 


217.9 


248.2 


261.2 


316 


317 


281.6 


145.7 


150.1 


149.1 


143.0 


207.7 


218.6 


249.0 


262.1 


317 


318 


282.5 


146.2 


150.7 


149.6 


143.5 


208.4 


219.3 


249.8 


262.9 


318 


319 


283.4 


146.7 


151.2 


150.1 


144.0 


209.0 


220.0 


250.6 


263.7 


319 


320 


284.2 


147.2 


151.7 


150.7 


144.5 


209.7 


220.7 


251.3 


264.6 


320 


321 


285.1 


147.7 


152.2 


151.2 


145.0 


210.4 


221.4 


252.1 


265.4 


321 


322 


286 . 


148.2 


152.7 


151.7 


145.5 


211.0 


222.2 


252.9 


266.2 


322 


323 


286.9 


148.7 


153.2 


152.2 


146.0 


211.7 


222.9 


253.7 


267.1 


323 


324 


287.8 


149.2 


153.7 


152.7 


146.6 


212.4 


223.6 


254.5 


267.9 


324 


325 


288.7 


149.7 


154.3 


153.2 


147.1 


213.1 


224.3 


255.3 


268.7 


325 


326 


289.6 


150.2 


154.8 


153.8 


147.6 


213.7 


225.0 


256.1 


269.6 


326 


327 


290.5 


150.7 


155.3 


154.3 


148.1 


214.4 


225.7 


256.9 


270.4 


327 


328 


291.4 


151.2 


155.8 


154.8 


148.6 


215.1 


226.4 


257.7 


271.2 


328 


329 


292.2 


151.7 


156.3 


155.3 


149.1 


215.8 


227.1 


258.5 


272.1 


329 


330 


293.1 


152.2 


156.8 


155.8 


149.7 


216.4 


227.8 


259.3 


272.9 


330 


331 


294.0 


152.7 


157.3 


156.4 


150.2 


217.1 


228.5. 


260.0 


273.7 


331 


332 


294.9 


153.2 


157.9 


156.9 


150.7 


217.8 


229.2 


260.8 


274.6 


332 


333 


295.8 


153.7 


158.4 


157.4 


151.2 


218.4 


230.0 


261.6 


275.4 


333 


334 


296.7 


154.2 


158.9 


157.9 


151.7 


219.1 


230.7 


262.4 


276.2 


334 


335 


297.6 


154.7 


159.4 


158.4 


152.3 


219.8 


231.4 


263.2 


277.0 


335 


336 


298.5 


155.2 


159.9 


159.0 


152.8 


220.5 


232.1 


264.0 


277.9 


336 


337 


299.3 


155.8 


160.5 


159.5 


153.3 


221.1 


232.8 


264.8 


278.7 


337 


338 


300.2 


156.3 


161.0 


160.0 


153.8 


221.8 


233.5 


265.6 


279.5 


338 


339 


301.1 


156.8 


161.5 


160.5 


154.3 


222.5 


234.2 


266.4 


280.4 


339 



16 



GENERAL METHODS AND CRUDE DRUG ASSAYS 



MUNSON AND WALKER'S TABLE— Continued 

Expressed in milligrams.] 



q 




'« 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


q 


=» 




8 
















3 


o 














O 


o 


9" 
Q 


3 

9 


3 


"3 

o 
H 


o 
H 




o 

E 




O 




'B 

o 


3 




O 


M 


fJ 03 


CO ^ 

S «3 


O 


6 


6 


5 


a 
3 


O 


0) 






A <*> 


§ M 




S3 




S 


O 


P. 

3 


& 
o 




<0 

> 


O 3 


2 3 


w 


w 


B 


a 


1 


o 


U 


Q 


*-* 


© 


<N 


6 


6 


o 


6 


O 


340 


302.0 


157.3 


162.0 


161.0 


154.8 


223.2 


234.9 


267.1 


281.2 


340 


341 


302.9 


157.8 


162.5 


161.6 


155.4 


223.8 


235.6 


267.9 


282.0 


341 


342 


303.8 


158.3 


163.1 


162.1 


155.9 


224.5 


236.3 


268.7 


282.9 


342 


343 


304.7 


158.8 


163.6 


162.6 


156.4 


225.2 


237.0 


269.5 


283.7 


343 


344 


305.6 


159.3 


164.1 


163.1 


156.9 


225.9 


237.8 


270.3 


284.5 


344 


345 


306.5 


159.8 


164.6 


163.7 


157.5 


226.5 


238.5 


271.1 


285.4 


345 


346 


307.3 


160.3 


165.1 


164.2 


158.0 


227.2 


239.2 


271.9 


286.2 


346 


347 


308.2 


160.8 


165.7 


164.7 


158.5 


227.9 


239.9 


272.7 


287.0 


347 


348 


309.1 


161.4 


166.2 


165.2 


159.0 


228.5 


240.6 


273.5 


287.9 


348 


349 


310.0 


161.9 


166.7 


165.7 


159.5 


229.2 


241.3 


274.3 


288.7 


349 


350 


310.9 


162.4 


167.2 


166.3 


160.1 


229.9 


242.0 


275.0 


289.5 


350 


351 


311.8 


162.9 


167.7 


166.8 


160.6 


230.6 


242.7 


275.8 


290.4 


351 


352 


312.7 


163.4 


168.3 


167.3 


161.1 


231.2 


243.4 


276.6 


291.2 


352 


353 


313.6 


163.9 


168.8 


167.8 


161.6 


231.9 


244.1 


277.4 


292.0 


353 


354 


314.4 


164.4 


169.3 


168.4 


162.2 


232.6 


244.8 


278.2 


292.8 


354 


355 


315.3 


164.9 


169.8 


168.9 


162.7 


233.3 


245.6 


279.0 


293.7 


355 


356 


316.2 


165.4 


170.4 


169.4 


163.2 


233.9 


246.3 


279.8 


294.5 


356 


357 


317.1 


166.0 


170.9 


170.0 


163.7 


234.6 


247.0 


280.6 


295.3 


357 


358 


318.0 


166.5 


171.4 


170.5 


164.3 


235.3 


247.7 


281.4 


296.2 


358 


359 


318.9 


167.0 


171.9 


171.0 


164.8 


236.0 


248.4 


282.2 


297.0 


359 


360 


319.8 


167.5 


172.5 


171.5 


165.3 


236.7 


249.1 


282.9 


297.8 


360 


361 


320.7 


168.0 


173.0 


172.1 


165.8 


237.3 


249.8 


283.7 


298.7 


361 


362 


321.6 


168.5 


173.5 


172.6 


166.4 


238.0 


250.5 


284.5 


299.5 


362 


363 


322.4 


169.0 


174.0 


173.1 


166.9 


238.7 


251.2 


285.3 


300.3 


363 


364 


323.3 


169.6 


174.6 


173.7 


167.4 


239.4 


252.0 


286.1 


301.2 


364 


365 


324.2 


170.1 


175.1 


174.2 


167.9 


240.0 


252.7 


286.9 


302.0 


365 


366 


325.1 


170.6 


175.6 


174.7 


168.5 


240.7 


253.4 


287.7 


302.8 


366 


367 


326.0 


171.1 


176.1 


175.2 


169.0 


241.4 


254.1 


288.5 


303.6 


367 


368 


326.9 


171.6 


176.7 


175.8 


169.5 


242.1 


254.8 


289.3 


304.5 


368 


369 


327.8 


172.1 


177.2 


176.3 


170.0 


242.7 


255.5 


290.0 


305.3 


369 


370 


328.7 


172.7 


177.7 


176.8 


170.6 


243.4 


256.2 


290.8 


306.1 


370 


371 


329.5 


173.2 


178.3 


177.4 


171.1 


244.1 


256.9 


291.6 


307.0 


371 


372 


330.4 


173.7 


178.8 


177.9 


171.6 


244.8 


257.7 


292.4 


307.8 


372 


373 


331.3 


174.2 


179.3 


178.4 


172.2 


245.4 


258.4 


292.2 


308.6 


373 


374 


332.2 


174.7 


179.8 


179.0 


172.7 


246.1 


259.1 


294.0 


309.5 


374 


375 


333.1 


175.3 


180.4 


179.5 


173.2 


246.8 


259.8 


294.8 


310.3 


375 


376 


334.0 


175.8 


180.9 


180.0 


173.7 


247.5 


260.5 


295.6 


311.1 


376 


377 


334.9 


176.3 


181.4 


180.6 


174.3 


248.1 


261.2 


296.4 


312.0 


377 


378 


335.8 


176.8 


182.0 


181.1 


174.8 


248.8 


261.9 


297.2 


312.8 


378 


379 


336.7 


177.3 


182.5 


181.6 


175.3 


249.5 


262.6 


297.9 


313.6 


379 


380 


337.5 


177.9 


183.0 


182.1 


175.9 


250.2 


263.4 


298.7 


314.5 


380 


381 


338.4 


178.4 


183.6 


182.7 


176.4 


250.8 


264.1 


299.5 


315.3 


381 


382 


339.3 


178.9 


184.1 


183.2 


176.9 


251.5 


264.8 


300.3 


316.1 


382 


383 


340.2 


179.4 


184.6 


183.8 


177.5 


252.2 


265.5 


301.1 


316.9 


383 


384 


341.1 


180.0 


185.2 


184.3 


178.0 


252.9 


266.2 


301.9 


317.8 


384 


385 


342.0 


180.5 


185.7 


184.8 


178. § 
179 . 1 


253.6 


266.9 


302.7 


318, 6 


385 


386 


342.9 


181.0 


186.2 


185.4 


254.2 


267.6 


303.5 


319.4 


386 


387 


343.8 


181.5 


186.8 


185.9 


179.6 


254.9 


268.3 


304.2 


320.3 


387 


388 


344.6 


182.0 


187.3 


186.4 


180.1 


255.6 


269.0 


305.0 


321.1 


388 


389 


345.5 


182.6 


187.8 


187.0 


180.6 


256.3 


269.8 


305.8 


321.9 


389 


390 


346.4 


183.1 


188.4 


187.5 


181.2 


256.9 


270.5 


306.6 


322.8 


390 


391 


347.3 


183.6 


188.9 


188.0 


181.7 


257.6 


271.2 


307.4 


323.6 


391 


392 


348.2 


184.1 


189.4 


188.6 


182.3 


258.3 


271.9 


308.2 


324.4 


392 


393 


349.1 


184.7 


190.0 


189.1 


182.8 


259.0 


272.6 


309.0 


325.2 


393 


394 


350.0 


185.2 


190.5 


189.7 


183.3 


259.6 


273.3 


309.8 


326.1 


394 



GENERAL METHODS 



17 



MUNSON AND WALKERS TABLE— Continued 

[Expressed in milligrams.] 



! 




n 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


O 

3 


o 




o 

3 
















Q 


e 
2 




3 


F4 


13 


"c3 




o 




O 


0J 

3 


M 

o 


9 1 
•o, 


T3 


c3 

t* 

3 
GO 

> 

a 


H 


O 




w 




W 


o 


! 
1 


U 

V 

a 
o 


s 

X 

0J 


a s 


S °s 

2 3 


O 


o 


5 

S 


' 9. 


3 
O 
Ph 

ft 

3 


O 


O 


A 


o" 


<N 


6 


6 


6 


u 


D 


395 


350.9 


185.7 


191.0 


190.2 


183.9 


260.3 


274.0 


310.6 


326.9 


395 


396 


351.8 


186.2 


191.6 


190.7 


184.4 


261.0 


274.7 


311.4 


327.7 


396 


397 


352.6 


186.8 


192.1 


191.3 


184.9 


261.7 


275.5 


312.1 


328.6 


397 


398 


353.5 


187.3 


192.7 


191.8 


185.5 


262.3 


276.2 


312.9 


329.4 


398 


399 


354.4 


187.8 


193.2 


192.3 


186.0 


263.0 


276.9 


313.7 


330.2 


399 


400 


355.3 


188.4 


193.7 


192.9 


186.5 


263.7 


277.6 


314.5 


331.1 


400 


401 


356.2 


188.9 


194.3 


193.4 


187.1 


264.4 


278.3 


315.3 


331.9 


401 


402 


357.1 


189.4 


194.8 


194.0 


187.6 


265.0 


279.0 


316.1 


332.7 


402 


403 


358.0 


189.9 


195.4 


194.5 


188.1 


265.7 


279.7 


316.9 


333.6 


403 


404 


358.9 


190.5 


195.9 


195.0 


188.7 


266.4 


280.4 


317.7 


334.4 


404 


405 


359.7 


191.0 


196.4 


195.6 


189.2 


267.1 


281.1 


318.5 


335 . 2 


405 


406 


360.6 


191.5 


197.0 


196.1 


189.8 


267.8 


281.9 


319.2 


336.0 


406 


407 


361.5 


192.1 


197.5 


196.7 


190.3 


268.4 


282.6 


320.0 


336.9 


407 


408 


362.4 


192.6 


198.1 


197.2 


190.8 


269.1 


283.3 


320.8 


337.7 


408 


409 


363.3 


193.1 


198.6 


197.7 


191.4 


269.8 


284.0 


321.6 


338.5 


409 


410 


364.2 


193.7 


199.1 


198.3 


191.9 


270.5 


284.7 


322.4 


339.4 


410 


411 


365.1 


194.2 


199.7 


198.8 


192.5 


271.2 


285.4 


323.2 


340.2 


411 


412 


366.0 


194. 7 


200.2 


199.4 


193.0 


271.8 


286.2 


324.0 


341.0 


412 


413 


366.9 


195.2 


2.(0.8 


199.9 


193 5 


272.5 


286 . 9 


324.8 


341.9 


413 


414 


367.7 


195.8 


201.3 


200.5 


194.1 


273.2 


287.6 


325.6 


342.7 


414 


415 


368.6 


196.3 


201.8 


201.0 


194.6 


273.9 


288 . 3 


326.3 


343.5 


415 


416 


369 . 5 


196.8 


202.4 


201.6 


195.2 


274.6 


289.0 


327.1 


344.4 


416 


417 


370.4 


197.4 


202.9 


202.1 


195.7 


275.2 


289.7 


327.9 


345.2 


417 


418 


371.3 


197.9 


203 . 5 


202.6 


196.2 


275.9 


290.4 


328.7 


346.0 


418 


419 


372 . 2 


198.4 


204.0 


203.2 


196.8 


276.6 


291.2 


329.5 


346.8 


419 


420 


373.1 


199.0 


204.6 


203.7 


197.3 


277.3 


291.9 


330.3 


347.7 


720 


421 


374.0 


199.5 


205.1 


204.3 


197.9 


277.9 


292.6 


331.1 


348.5 


421 


422 


374.8 


200 1 


205.7 


204.8 


198.4 


278.6 


293.3 


331.9 


349.3 


422 


423 


375.7 


200.6 


206.2 


205.4 


198.9 


279.3 


294.0 


332.7 


350.2 


423 


424 


376.6 


201.1 


206.7 


205.9 


199.5 


280.0 


294.7 


333.4 


351.0 


424 


425 


377.5 


201.7 


207.3 


206.5 


200.0 


280.7 


295.4 


334.2 


351.8 


425 


426 


378.4 


202.2 


207.8 


207.0 


200.6 


281.3 


296.2 


335.0 


352.7 


426 


427 


379.3 


202.8 


208.4 


207.6 


201.1 


282.0 


296.9 


335.8 


353.5 


427 


428 


380.2 


203.3 


208.9 


208.1 


201.7 


282.7 


297.6 


336.6 


354.3 


428 


429 


381.1 


203.8 


209.5 


208.7 


202.2 


283 . 4 


298.3 


337.4 


355.1 


429 


430 


382.0 


204.4 


210.0 


209.2 


202.7 


284.1 


299.0 


338.2 


356.0 


430 


431 


382.8 


204.9 


210.6 


209.8 


203.3 


284.7 


299.7 


339.0 


356.8 


431 


432 


383 . 7 


205.5 


211.1 


210.3 


203.8 


285.4 


300.5 


339.7 


357.6 


432 


433 


384.6 


206.0 


211.7 


210.9 


204.4 


286.1 


301.2 


340.5 


358.5 


433 


434 


385.5 


206.5 


212.2 


211.4 


204.9 


286.8 


301.9 


341.3 


359.3 


434 


435 


386.4 


207.1 


212.8 


212.0 


205.5 


287.5 


302.6 


342.1 


360.1 


435 


436 


387.3 


207.6 


213.3 


212.5 


206.0 


288.1 


303.3 


342.9 


361.0 


436 


437 


388.2 


208.2 


213.9 


213.1 


206.6 


288.8 


304.0 


343.7 


361.8 


437 


438 


389.1 


208.7 


214.4 


213.6 


207.1 


289.5 


304.7 


344.5 


362.6 


438 


439 


390.0 


209.2 


215.0 


214.2 


207.7 


290.2 


305.5 


345.3 


363.4 


439 


440 


390.8 


209.8 


215.5 


214.7 


208.2 


290.9 


306.2 


346.1 


364.3 


440 


441 


391.7 


210.3 


216.1 


215.3 


208.8 


291.5 


306.9 


346.8 


365.1 


441 


442 


392.6 


210.9 


216.6 


215.8 


209.3 


292.2 


307.6 


347.6 


365.9 


442 


443 


393.5 


211.4 


217.2 


216.4 


209.9 


292.9 


308.3 


348.4 


366.8 


443 


444 


394.4 


212.0 


217.8 


216.9 


210.4 


293.6 


309.0 


349.2 


367.6 


444 


445 


395.3 


212.5 


218.3 


217.5 


211.0 


294.2 


309.7 


350.0 


368.4 


445 


446 


396.2 


213.1 


218.9 


218.0 


211.5 


294.9 


310.5 


350.8 


369.3 


446 


447 


397.1 


213.6 


219.4 


218.6 


212.1 


295.6 


311.2 


351.6 


370.1 


447 


448 


397.9 


214.1 


220.0 


219.1 


212.6 


296.3 


311.9 


352.4 


370.9 


448 


449 


398.8 


214.7 


220.5 


219.7 


213.2 


297.0 


312.6 


353.2 


371.7 


449 

























18 GENERAL METHODS AND CRUDE DRUG ASSAYS 

MUNSON AND WALKER'S TABLE— Continued 

[Expressed in milligrams.] 



6 




<v 




Invert Sugar 
and Sucrose 


Lactose 


Maltose 


6 


3 




01 

O 
« 

3 
















3 


o 




t 










O 


01 

12 


_ 


3 


«i 


o 


"3 




O 




O 


o 


'x 

O 


'a 
O 


3 




H 


o 




w 




«' 


o 


OB 

3 






W 




5 ** 
a «8 


q 


q 


q 


3 

q 


5 


O 


a 
c 
o 


0> 


u 
> 

£5 


6% 


2 3 

0«2 


S 


1 


1 


1 


o 

u 
ft 

3 


o 


O 


Q 




© 


<N 


d 


3 


Q 


d 


o 


450 


399.7 


215.2 


221.1 


220.2 


213.7 


297.6 


313.3 


353.9 


372.6 


450 


451 


400.6 


215.8 


221.6 


220.8 


214.3 


298.3 


314.0 


354.7 


373.4 


451 


452 


401.5 


216.3 


222.2 


221.4 


214.8 


299.0 


314.7 


355.5 


374.2 


452 


453 


402.4 


216.9 


222.8 


221.9 


215.4 


299.7 


315.5 


356.3 


375.1 


453 


454 


403.3 


217.4 


223.3 


222.5 


215.9 


300.4 


316.2 


357.1 


375.9 


454 


455 


404.2 


218.0 


223.9 


223.0 


216.5 


301.1 


316.9 


357.9 


376.7 


455 


456 


405.1 


218.5 


224.4 


223.6 


217.0 


301.7 


317.6 


358.7 


377.6 


456 


457 


405.9 


219.1 


225.0 


224.1 


217.6 


302.4 


318.3 


359.5 


378.4 


457 


458 


406.8 


219.6 


225.5 


224.7 


218.1 


303.1 


319.0 


360.3 


379.2 


458 


459 


407.7 


220.2 


226.1 


225.3 


218.7 


303.8 


319.8 


361.0 


380.0 


459 


460 


408.6 


220.7 


226.7 


225.8 


219.2 


304.5 


320.5 


361.8 


380.9 


460 


461 


409.5 


221.3 


227.2 


226.4 


219.8 


305.1 


321.2 


362.6 


381.7 


461 


462 


410.4 


221.8 


227.8 


226.9 


220.3 


305.8 


321.9 


363.4 


382.5 


462 


463 


411.3 


222.4 


228.3 


227.5 


220.9 


306.5 


322.6 


364.2 


383.4 


463 


464 


412.2 


222.9 


228.9 


228.1 


221.4 


307.2 


323.4 


365.0 


384.2 


464 


465 


4i3.0 


223.5 


229.5 


228.6 


222.0 


307.9 


324.1 


365.8 


385.0 


465 


466 


413.9 


224.0 


230.0 


229.2 


222.5 


308.6 


324.8 


366.6 


385.9 


466 


467 


414.8 


224.6 


230.6 


229.7 


223.1 


309.2 


325.5 


367.3 


386.7 


467 


468 


415.7 


225.1 


231.2 


230.3 


223.7 


309.9 


326.2 


368.1 


387.5 


468 


469 


416.6 


225.7 


231.7 


230.9 


224.2 


310.6 


326.9 


368.9 


388.3 


469 


470 


417.5 


226.2 


232.3 


231.4 


224.8 


311.3 


327.7 


369.7 


389.2 


470 


471 


418.4 


226.8 


232.8 


232.0 


225.3 


312.0 


328.4 


370.5 


390.0 


471 


472 


419.3 


227.4 


233.4 


232.5 


225.9 


312.6 


329.1 


371.3 


390.8 


472 


473 


420.2 


227.9 


234.0 


233.1 


226.4 


313.3 


329.8 


372.1 


391.7 


473 


474 


421.0 


228.5 


234.5 


233.7 


227.0 


314.0 


330.5 


372.9 


392.5 


474 


475 


421.9 


229.0 


235.1 


234.2 


227.6 


314.7 


331.3 


373.7 


393.3 


475 


476 


422.8 


229.6 


235.7 


234.8 


228.1 


315.4 


332.0 


374.4 


394.2 


476 


477 


423.7 


230.1 


236.2 


235.4 


228.7 


316.1 
316.7 


332.7 


375.2 


395.0 


477 


478 


424.6 


230.7 


236.8 


235.9 


229.2 


333.4 


376.0 


395.8 


478 


479 


425.5 


231.3 


237.4 


236.5 


229.8 


317.4 


334.1 


376.8 


396.6 


479 


480 


426.4 


231.8 


237.9 


237.1 


230.3 


318.1 


334.8 


377.6 


397.5 


480 


481 


427.3 


232.4 


238.5 


237.6 


230.9 


318.8 


335.6 


378.4 


398.3 


481 


482 


428.1 


232.9 


239.1 


238.2 


231.5 


319.5 


336.3 


379.2 


399.1 


482 


483 


429.0 


233.5 


239.6 


238.8 


232.0 


320.1 


337 . 


380.0 


400.0 


483 


484 


429.9 


234.1 


240.2 


239.3 


232.6 


320.8 


337.7 


380.7 


400.8 


484 


485 


430.8 


234.6 


240.8 


239.9 


233.2 


321.5 


338.4 


381.5 


401.6 


485 


486 


431.7 


235.2 


241.4 


240.5 


233.7 


322.2 


339.1 


382.3 


402.4 


486 


487 


432.6 


235.7 


241.9 


241.0 


234.3 


322.9 


339.9 


383.1 


403.3 


487 


488 


433.5 


236.3 


242.5 


241.6 


234.8 


323.6 


340.6 


383.9 


404.1 


488 


489 


434.4 


236.9 


243.1 


242.2 


235.4 


324.2 


341.3 


384.7 


404.9 


489 


490 


435.3 


237.4 


243.6 


242.7 


236.0 


324.9 


342.0 


385.5 


405.8 


490 



COMMERCIAL GLUCOSE 
Method I. — Tentative. — A.O.A.C. 

(Substances containing Utile or no invert sugar.) 

Commercial glucose cannot be determined accurately owing to the 
varjdng amounts of dextrin, maltose, and dextrose present in this prod- 
uct. However, in syrups, in which the amount of invert sugar is so 



GENERAL METHODS 19 

small as not to appreciably affect the result, commercial glucose may be 
estimated approximately by the following formula: 

n (a- S) 100 
G= 175 ' 
in which 

(r = per cent of commercial glucose; 
a = direct polarization ; 
S = per cent of cane sugar. 

Express the results in terms of commercial glucose polarizing -}-175 V. 

Method II. — Tentative. — A.O.A.C. 

(Substances containing invert sugar.) 

Prepare an inverted half-normal solution of the substance as directed 
under " Sucrose," except that after inversion cool the solution, make 
neutral to phenolphthalein with sodium hydroxid solution, slightly acid- 
ify with hydrochloric acid, and treat with 5-10 mils of alumina cream 
before making up to the mark. Filter and polarize at 87° C. in a 200-mm. 
jacketed tube. Multiply the reading by 200 and divide by the factor 
163 to express the amount of glucose present in terms of glucose polari- 
zing + 175° V, 

ARSENIC 

It is a good rule for the analyst in the field of medicinal chemistry to 
test every mixture for arsenic. In the more common forms, as arsenous 
acid, arsenic iodide, bromide, chloride, peptonate, or sulphide, the amount 
given at a dose is selclom more than -£$ - \ of a grain, and from that amount 
it dwindles down to two- During recent } r ears it has been the custom 
to administer this element in some organic combination where, compar- 
atively, the dose of the metal is much larger, thus in salvarsan many 
times the lethal dose can be tolerated than if in simple ionic condition. 
Again, its presence will be manifested in unexpected cases as an impurity, 
for instance in the coating of tablets where oxide of iron has been substi- 
tuted for chocolate. 

The Pharmacopoeia prescribes a method for the assay of Fowler's solu- 
tion, and there are procedures given for the examination of salvarsan and 
other pure organic substances which will be detailed later, but at this 
point we are concerned with the testing of mixtures containing arsenic. 
The simplest procedure for its determination is by a comparative Marsh 
mirror or mercuric chloride test paper. In this determination the steps 
include a careful oxidation of the organic matter, the manipulation of a 
Marsh test with the clear solution obtained by oxidation, and the com- 



20 GENERAL METHODS AND CRUDE DRUG ASSAYS 

parison of the mirror or stain with a set of standards. The oxidation 
may be carried out with nitric and sulphuric acid, though Bishop claims 
that there is loss of arsenic by volatilization and advocates a modified 
oxidation which is subsequently described. 

If the substance is a solid, 5 to 10 grams are weighed out and treated 
directly in a No. VI porcelain dish with 25-50 mils arsenic-free nitric acid 
and allowed to digest in the cold until the organic matter and most of 
the soluble mineral matter have gone into solution. If a liquid prepara- 
tion is under examination, 25-50 mils should be evaporated over the steam 
bath and the residue treated with nitric acid. By this procedure a clear 
yellow to reddish liquid usually results, and the subsequent manipulation 
is greatly facilitated. The nitrated mixture is now treated with 15 mils 
of concentrated sulphuric acid and stirred cautiously without warming; 
if sugar is present in any great amount, there will be an energetic action 
and if there is danger of loss by contents frothing over, strong nitric acid 
should be quickly added in considerable quantity and the action will sub- 
side immediately. If the heat generated by the action is sufficient to 
drive off all the remaining nitric acid the residue will now be black, and 
a further quantity should be added, well mixed, and the dish carefully 
warmed over a low flame or on an electric hot plate running at a moder- 
ate temperature and covered with a watch glass. The charred residue 
will quickly decolorize, and if no subsequent charring takes place when 
the nitric acid is driven off, the procedure may be terminated, but if char- 
ring occurs again, the dish must be cooled, more nitric acid added and the 
heat again applied and this manipulation continued until a clear residue 
remains. 

When the residue becomes cold it is transferred to a graduated flask 
of 100 mils capacity and made up to the mark with water. Aliquots of 
this solution are then introduced into the Marsh apparatus until a mirror 
is obtained which is suitable for comparison. 

Individual workers usually prefer their own style of Marsh apparatus, 
and the author will not attempt to describe the multitudinous arrange- 
ments which are to be found in the different laboratories. If the worker 
uses the mirror test it is important that the glass be sufficiently hard to 
withstand a high heat, if not the tube will probably fuse and seal up and 
the stopper blow out of the generator or the tube may be kept too cool 
and some of the arsenic escape. The glass recommended is that having 
a bluish fluorescence when examined longitudinally. 

Two simple forms of apparatus and attachments are shown in the 
accompanying illustrations. 

A is the generator fitted with a two-hole rubber stopper containing 
a small bulb separatory funnel and a bent tube B shown in greater detail 
on the side. The latter contains a loose wad of dry lead acetate paper, 



GENERAL METHODS 



21 



then a small pledget of cotton, then granular calcium chloride and another 
small pledget of cotton. To this tube is attached the mirror tube of 
hard glass D, of about \ to | in. inside diameter, which rests on a tripod, 
and is surrounded about 1 in. from the capillary end with a roll of copper 
gauze E, 2 in. wide. The tube is heated by a Bunsen burner fitted with 
a wing top. To start the apparatus use powdered 20-mesh zinc C. P. 



6 



*c 



V7 



free from arsenic and sulphuric acid 1-3. When beginning work with a 
newly constructed apparatus, the evolution of hydrogen will be extremely 
slow, often practically stagnant, but the introduction of a few drops of 
copper sulphate solution will start an energetic and steady evolution. 
After the apparatus has run for about eight minutes, the Bunsen should 
be lighted and observations made as to the purity of the reagents. If 
there is no deposit, the aliquot of the 
unknown mixture may be introduced 
through the separatoiy funnel and 
washed down into the generator with 
sulphuric acid 1-3. 

It is not necessary to light the gas 
escaping at the outlet of the capillary 
tube. 

When using the bichloride test- 
paper prepared by dipping strips of 
filter paper into a 5 per cent alcoholic 
solution of HgCl 2 , the same form 

of generator and clarifying tube can be used and the combustion tube 
substituted by an ordinary glass tube into which the strip of test-paper 
is inserted. Every laboratory should have a set of standard mirrors or 
bichloride test-papers, prepared from a carefully standardized solution of 
arsenous acid, and they should be kept in the dark and replaced from 
time to time by new ones. 

Bishop's 1 method is applicable to those substances which are soluble 
in or decomposed by hot concentrated sulphuric acid. A mixture of 
1 Jour. Amer. Chem. Soc, 28, 1906, 178-185. 




22 GENERAL METHODS AND CRUDE DRUG ASSAYS 

hydrochloric and sulphurous acids is forced through a capillary tube into 
the hot sulphuric acid. After distilling for one hour while absorbing the 
escaping gas in water, the distillate containing arsenous chloride, hydro- 
chloric and sulphurous acid, is oxidized with potassium chlorate, evapo- 
ated on the steam bath and the Marsh test applied. 

Andrews and Farr 1 offer a volumetric method for estimating small 
quantities of arsenic which could probably be used after separating the 
arsenic from the other ingredients by oxidation or distillation. About 
20 mils of the solution are mixed with 50 mils of a solution of 20 grams 
of stannous chloride and 40 grams tartaric acid in 1 liter 40 per cent hydro- 
chloric acid, and the mixture heated for two to three hours at 35-40° C. 
in a well-stoppered bottle, until the precipitated arsenic has completely 
settled. The precipitate is washed onto an asbestos filter with the aid 
of strong hydrochloric acid free from chlorine and then the filter and pre- 
cipitate are returned to the bottle with an amount of N/100 or N/10 
iodine solution 10-100 per cent above that indicated by the equation: 

As+5I+7 NaHC0 3 = Na 2 HAs04+5NaI+7 C0 2 +3 H 2 

Enough of a 5 per cent solution of sodium bicarbonate or phosphate is 
added to maintain neutrality, and when all the arsenic is dissolved, the 
excess of iodine is titrated with N/100 or N/1000 arsenite solution. For 
quantities of arsenic smaller than 0.5 milligram, N/1000 solution may be 
used, but in this case a correction must be made for the amount of iodine 
required to produce the end reaction. 

^mer. Jour. Sci., 1909, 27, 316-20. 



CHAPTER II 

CRUDE DRUG ASSAYS 

Drug assaying requires a special technique which is acquired only after 
considerable experience. An accurate analyst understands the theory 
of the process and knows the reason for each step in the manipulation. 
Assay methods tty the legion have been proposed and many of them have 
been studied by referees working with corps of collaborators. The results 
have sometimes shown wide variation and the reason is due sometimes 
to faults in the methods, but more often to the personal equation of the 
operators. It is the author's conclusion, after studying the results obtained 
by different workers on a given sample, that a wide variation in figures 
usually could be traced directly to inattention to details which are abso- 
lutely necessary in carrying out these delicate determinations. Analysts 
will offer themselves as competent to handle alkaloid assaying w r ho have 
had practically no experience with drugs and perhaps none in handling 
the special apparatus required. The}'' run through a single assay of a 
drug without preliminary practice and report their results to the con- 
sternation of the referee. There is no field of chemical work where one 
needs longer and more exact training than in manipulating alkaloids. It 
is admitted that in describing methods, little details essential for correct 
results are often omitted, and it might be assumed that a worker with 
chemical " sense " should be aware of them in their proper place, but 
this is not the case, and in nine cases out of ten they will be neglected. 
For instance, after shaking out the original percolate with acid, this acid 
solution should be shaken thoroughly with ether and allowed to separate 
completely, at least fifteen minutes, then run into another separator, the 
ether washed with a little water and this added to the acid, the solution 
being then ready for the alkali. Again, in all titration methods there 
is a considerable opportunity for error by dissolving in N/10 acid, using 
only 3-5 c.c. It would be better to dissolve in 20 c.c. of N/50 acid, which 
will reduce the error to a minimum, or if it is feared that a weak acid will 
not completely take up the alkaloid, dissolve the residue in neutral alco- 
hol, adding acid and then titrating back; or if neutral alcohol is not feasi- 
ble, dissolve in ordinary alcohol and run a blank. When a drug is shaken 
with a volatile solvent in a flask and then poured into a percolator, the 

23 



24 GENERAL METHODS AND CRUDE DRUG ASSAYS 

lip of the flask should be carefully washed with an additional quantity of 
solvent in order to remove any adhering alkaloid, which is always 
left there by the evaporation of the menstruum. The stem of the 
separator should be washed in the same way, and in all cases where the 
solvent containing the alkaloid is run from a separator into a dish for 
final evaporation, the stem of the separator should be carefully washed. 
If the solvent solution containing the alkaloid is filtered before evapora- 
tion, the filter paper should be thoroughly washed and the stem of the 
funnel also, and the filter paper should not entirely fill the funnel. 

It has been questioned whether it is advisable to put all these details 
into the text of the assay of every drug, but instead, to describe a typical 
method in detail and then adapt each drug to it under its own heading. 
Future compilers will some day settle this point, but no method is too 
long to read and digest if correct results are desired, and a method is worth- 
less unless it gives a correct valuation of the drug. 

The apparatus required in drug assaying will include a stock of sepa- 
ratory funnels with stopcocks and stoppers carefully and evenly ground 
to fit tightly and not stick, the most convenient being those of the 4-oz. 
Squibb type, with several extra of the small and larger sizes. To sup- 
port these when in the works one of the simplest and most efficient arrange- 
ments consists of a number of vertical iron rods bolted about 6 in. apart 
onto a wooden platform, fitted with a set of ordinary rings and clamps, 
the rings being of different sizes to accommodate different-size separators, 
and cut in the circumference directly opposite the clamp. By covering 
the metal with ordinary Bunsen burner tubing, a firm and safe resting 
place is provided for the separators. 

The evaporation of the solvent containing the alkaloid is conven- 
iently carried out in beakers of 100-150 mils capacity. They are small 
enough to tare and yet large enough to hold any volume of solvent con- 
taining the final shake out of an assay. 

The maceration and shaking of the ground drug before introduction 
into the percolator can be conducted to advantage in an 8-oz. nursing 
bottle. The glass is hard and a stopper can be inserted firmly into the 
neck and rendered practically immovable by tying, 

Percolators of glass for this class of work are now obtainable from 
apparatus supply houses. 

Maceration and shaking out of the ground drug is best accomplished 
by means of a mechanical shaker, the details of which are apparent from 
the accompanying diagram. This apparatus should be constructed so 
that it may be tipped on its side and the disk inclined at an angle, for in 
certain extraction methods later in the work, where one is handling mix- 
tures prone to emulsify, a turtle-shaped separatory funnel is necessary, 
thus giving a large surface of contact. When at rest this form of separator 



CRUDE DRUG ASSAYS 



25 





26 



GENERAL METHODS AND CRUDE DRUG ASSAYS] 



is held in an upright position by a frame consisting of a board back with 

two screws set perpendicularly to the plane of the board and which can 

be turned sufficiently to tightly but securely clamp 

(] the separator. 

For many years cochineal has been a favorite 
indicator for alkaloidal titration, but the introduction 
of methyl red, which is now easily obtainable from chemical supply 
houses, has largely superseded cochineal and is to be preferred. 




ACONITE 

The assay of this drug has always been a matter of controversy. There 
are two points to be considered — whether it is a question of reporting 
the total content of basic principles or to ascertain only the therapeutic 
activity. Aconitin (ethyl-benzoyl aconin) , benzoyl aconin, and aconin are 
the principal basic components of commercial aconite, and whether the 
alkaloidal content was wholly aconitin in the fresh drug is a subject yet 
to be determined; the drug assayist meets with a mixture of bases and 
the proportions vary. It is apparent that the therapeutic efficiency is due 
almost solely to the aconitin, and as yet there has been no satisfactory 
chemical method evolved for determining this body in a mixture of its 
degradation products. Taylor 1 has studied the different problems con- 
nected with assaying aconite from the viewpoint of determining its act- 
ual therapeutic value, and concludes that a chemical method, using ether 
alone, is the only one of any value for obtaining a measure of the aconitin, 
and that even the residue from an ether extraction contains other basic 
l J. Ind. Eng. Chem, 1, 1909, 549. 



CRUDE DRUG ASSAYS 27 

principles in greater or less part but never constant; thus the determi- 
nation of the total alkaloids is of no value as a measure of the aconitin, 
and that in order to obtain a true indication of the medicinal value of 
aconite or any of its preparations the Squibb physiological test should 
be employed. The latter is in fact very simple and easy of manipula- 
tion and gives reliable results after a little practice. 

Method of the U. S. P. — Ninth Revision. — The method of the ninth 
revision is a distinct advance over that in the eighth revision, where the 
results were neither a measure of the therapeutic activity nor of the basic 
constituents. 

Aconite in No. 40 powder is used and the amounts taken and manipu- 
lation of the assay are the same as under Belladonna Leaves, except that 
ether is used throughout. Each mil of N/50 sulphuric acid consumed 
corresponds to 12.9 milligrams of ether-soluble alkaloids. 

The Squibb Test. 1 — Dilute the fluid extract or the percolate from the 
ground drug adjusted to fluid extract volume, in such proportion that 
T V minim will be contained in 1 fluid dram of water. Rinse out the mouth 
well to free the surfaces from mucus and saliva and hold the above one 
dram of dilution in the anterior part of the mouth for exactly one minute 
and then discharge it. A distinct tingling sensation should be perceived 
within ten to fifteen minutes. 

Taylor says, and my own practice agrees with his, that " the above 
dilution is in proportion of one part of fluid extract to 600 parts water. 
In laboratory practice it is better to require the fluid extract of the drug 
to respond in dilution of 1 in 700, the fluid extract of leaves 1 in 100, the 
extract of root 1 in 3000, and aconitin 1 in 500,000. In the application 
of the test, dilute 10 mils of the fluid or 1 gram of the extract to the cal- 
culated volume, using water acidulated with acetic acid in the first step 
and pure water for the final dilution. " 



ANHALONIUM 

The Mescale button contains a number of well-defined alkaloids, and 
the drug has some use in medicine. To determine the total alkaloids, 5 
grams of the powdered drug or 5 mils of the extract evaporated on saw- 
dust are well shaken with 150 mils Prolius mixture (ether 4, chloroform 
1, alcohol 1) and 4 mils ammonia water; 50 mils of the solvent are filtered 
into a separator and exhausted with 2 per cent hydrochloric acid, the 
latter is then washed with petroleum ether, which is discarded, and then 
made alkaline with ammonia and extracted with ether-chloroform 1-1. 
The solvent is filtered into a tared dish, evaporated, dried, and weighed. 

iEphemeris 1, 126 and 3, 293. 



28 GENERAL METHODS AND CRUDE DRUG ASSAYS 

ASPIDOSPERMA 

While this drug does not have an extended use in medicine it contains 
well-defined bases, and an assay of the total alkaloidal content is not dif- 
ficult. Twenty grams of the ground drug or 20 mils of the extract evap- 
orated on sawdust are treated in a flask or bottle with 150 mils of petro- 
leum ether-chloroform 2-1 and 4 mils ammonia, and thoroughly shaken; 
75 mils of the clear liquid are filtered into a separator and shaken out 
with 2 per cent hydrochloric acid, the acid solution is washed once with 
petroleum ether which is discarded and then made alkaline with ammonia 
and shaken out with ether. The solvent is separated and filtered into 
a tared dish, evaporated and the residue dried at 100° C. and weighed. 

BELLADONNA 

The method of the U. S. Pharmacopoeia, eighth revision, for this drug 
is in the main very satisfactory, and gives more accurate information as 
to the true alkaloidal content of the drug than the method of the ninth 
revision. It is essential that the acid shake-out should be washed with 
the ether-chloroform mixture before adding ammonia, and the final chloro- 
form solution should be run through cotton lightly plugged into the stem 
of the separator when the alkaloidal residue will be in much better shape 
for titration. 

U. S. P., Eighth Revision. — Place ten grams of Belladonna leaves or 
root in No. 60 powder in an Erlenmeyer flask, and add 50 mils of a mix- 
ture of chloroform 1 part and ether 4 parts (both by volume) After 
inserting the stopper securely allow the flask to stand ten minutes, then 
add 2 mils of ammonia water mixed with 3 mils of distilled water, and shake 
the flask well at frequent intervals during one hour. Then transfer as 
much as possible of the contents of the flask to a small percolator which 
has been provided with a pledget of cotton packed firmly in the neck 
and inserted in a separator containing 6 mils of normal sulphuric acid V. 
S. diluted with 20 mils of distilled water. When the liquid has passed 
through the cotton, pack the Belladonna leaves firmly in the percolator 
with the aid of a glass rod, and having rinsed the flask with 10 mils of the 
chloroform-ether mixture, transfer the remaining contents of the flask 
to the percolator, by the aid of several small portions (5 mils) of the chloro- 
form-ether mixture, and continue the percolation with successive small 
portions of the same liquid (using in all 50 mils) . Next, shake the sepa- 
rator well for one minute, after securely inserting the stopper, and when 
the liquids have completely separated, draw off the acid solution into 
another separator. Add to the chloroform-ether mixture 10 mils of sul- 
phuric acid mixture of the same strength as that previously used, agitate 
well, and again draw off the acid solution into the second separator; repeat 



CRUDE DRUG ASSAYS 29 

this operation once more, drawing off the acid solution as before; intro- 
duce into the acid solutions contained in the second separator a small 
piece of red litmus paper, then add ammonia water until the liquid is 
distinctly alkaline, and shake out with three successive portions of chloro- 
form 15, 15, and 5 mils; collect the chloroform solutions in a beaker, 
place it on a water-bath containing warm water, and allow the chloro- 
form to evaporate entirely. Dissolve the residue in 3 mils of ether, and 
let this also evaporate completely. To the alkaloidal residue add 3 mils 
of N/10 sulphuric acid V. S. and 5 drops of cochineal T. S. (or iodeosin 
T. S.), then titrate the excess of acid with N/50 potassium hydroxide 
V. S. Divide the number of mils of N/50 potassium hydroxide V. S. 
used, by 5, subtract the quotient from 3 (the 3 mils of N/10 sulphuric 
acid V. S. taken) and multiply the remainder by 0.0287 and this product 
by 10; the result will be the percentage of total mydriatic alkaloids 
contained in the Belladonna leaves, or root. 

U. S. P., Ninth Revision. — Introduce 15 grams of Belladonna leaves 
or root in No. 60 powder into a flask of 250 mils capacity and add 150 
mils of a mixture of chloroform 1 volume and ether 2 volumes. Stopper 
the flask, shake it well and allow it to stand ten minutes, then add 5 mils 
ammonia water and shake vigorously every ten minutes during two hours; 
now add 15 mils distilled water (25 mils in case of leaf), again shake the 
flask well and when the drug has settled, decant 100 mils of the solution, 
representing 10 grams of the drug. 

Filter the solution through a pledget of cotton wool into a separator 
and rinse the graduate and cotton with a little ether. Completely extract 
the alkaloids from the chloroform-ether solution by shaking out repeatedly 
with weak sulphuric acid. Collect the acid washings in a separator, add 
ammcnia water until the solution is distinctly alkaline and completely 
extract the alkaloids by shaking out repeatedly with chloroform. Evap- 
rate the combined chloroform washings to dryness (in case of leaf treat 
twice with 5 mils ether), add exactly 5 mils of N/10 sulphuric acid to the 
residue and titrate the excess of acid with N/50 potassium hydroxide 
using cochineal T. S. as indicator. Each mil of N/10 sulphuric acid con- 
sumed corresponds to 28.2 milligrams of total alkaloids. 

Javallier 1 has studied the compound of atropin with silicotungstic 
acid and recommended a method for assaying belladonna and its extracts. 
The solution of the alkaloid should not be too dilute, as the precipitate 
is not completely insoluble in water. Hydrochloric acid is added to the 
solution in such quantity that 2 per cent of free acid is present, and then 
a 10 per cent solution of silicotungstic acid or its potassium salt is added 
drop by drop, with stirring; excess of the reagent must be avoided. After 
standing for twenty-four hours the precipitate is separated by nitration 
1 Bull. Sci. Pharmacol., 1910, 17, 629-34. 



30 GENERAL METHODS AND CRUDE DRUG ASSAYS 

or in a centrifugal apparatus, washed with 1 per cent hydrochloric acid, 
and incinerated. The weight, multiplied by 0.4064, gives the quantity 
of atropin, to which 0.0048 gram for each 100 mils of the original solu- 
tion is added as a correction for the solubility of the atropin silicotung- 
state (the solubility in the wash water may be disregarded). Precipi- 
tation may be effected in hot or cold solutions, but prolonged boiling 
must be avoided. The method can be used for the determination of atro- 
pine in belladonna extract. 

CANNABIS SATTVA 

U. S. P., Ninth Revision. — The method consists of ascertaining the dose 
of the preparation to be tested which will produce symptoms of incoor- 
dination in dogs and then adjusting its strength by comparison with a 
standard preparation. 

Dogs. — The animals differ considerably in susceptibility to the drug 
and therefore it is best to make preliminary tests upon several dogs with 
average-sized doses and select from among them the animals which react 
easily to the drug. As a rule, fox terriers serve verj^ well for the purpose, 
but any dog may prove satisfactory. It is best to provide at least two 
dogs for each assay, but if many samples are to be examined more dogs 
will be needed. The dogs should be at least one year old and in normal 
health and must be kept under the best sanitary conditions. They may 
be used repeatedly for the purpose but not at shorter intervals than three 
days. Each series of tests should be conducted by the same person, who 
should be perfectly familiar with the peculiarities of each animal in order 
that he may recognize more certainly deviations from the normal. While 
the tests are being made the animals should be kept in a perfectly quiet 
room, free from disturbance and separated so that they cannot see each 
other. 

Preparation of the Drug. — The drug may be given most conveniently 
in the form of the fluid extract, which is administered in gelatin capsules, 
or the extract made into soft pills may be used; but whichever form is 
chosen the same should be used for both the standard and the prepara- 
tion that is to be tested. 

Before administration the animal should not be fed for twenty-four 
hours in order to hasten absorption. The head of the animal being held, 
its mouth is opened and the capsule or pill is placed upon the back of the 
tongue. Usually the drug is easily swallowed when given in this way, 
but this may be facilitated by giving the animal a small amount of water 
to drink. 

Assay. — An average dose of the known or standard preparation is 
given to one of the dogs and a like dose of the preparation to be standard- 



CRUDE DRUG ASSAYS 31 

ized is given the second dog. After one hour both dogs are observed very 
carefully for symptoms of muscular incoordination. The incoordination 
is manifested differently in different animals, but in small doses it shows 
itself most frequently in slight swaying, when the animal is standing 
quietly, or in some ataxia when it runs about. The observation should 
be made frequently dining the second hour following the administration 
of the drug. 

The results obtained from the first test should be confirmed after an 
interval of not less than three days by repeating the administration but 
reversing the order, that is, giving the known strength drug to the dog 
which received that of unknown strength before and vice versa. 

In subsequent tests which are carried out, the dose of the preparation 
of unknown strength is modified so as to produce similar symptoms to 
those produced by the standard. If the preparation to be tested is below 
the standard in strength, its dose must be increased, or if it is above strength 
its dose is lessened until equivalent doses of the two are found. Dogs may 
be used over long periods of time, even for some years, but occasionally 
they have to be discarded, as in some cases they seem to learn the effects 
of the drug and so refuse to stand up. A certain degree of tolerance is 
sometimes gained which necessitates larger doses. 

Standard. — As there is no chemical substance of definite composi- 
tion which can be adopted as a standard, a fluid extract of Cannabis or 
an extract which has been carefully prepared and suitably preserved may 
be utilized for this purpose. A standard fluid extract will produce inco- 
ordination when administered to dogs in the dose of 0.03 mil for each 
kilogram of body weight of dog. When administered in the form of the 
extract a dose of 0.004 gram for each kilogram of body weight of dog 
should produce similar symptoms, and the requirement for a standard 
tincture is a dose of 0.3 mil for each kilogram of body weight of dog. 

CANTHARIDES 

Cantharidin occurs partly free and partly combined in several differ- 
ent species of beetles. Many assay methods have been proposed for its 
determination, and a comparative study of the different methods was 
made by Kneip, Ney and Reimers. 1 These authors then developed three 
new procedures, the essentials of which are as follows: 

(1) Powdered cantharides is extracted with chloroform in the pres- 
ence of nitric acid, the solvent carefully evaporated, the residue washed 
with petroleum ether, then with ether and alcohol saturated with can- 
tharidin, then dissolved in chloroform, the solvent evaporated and dried 
at 60° C. for one hour. 

iArch. Pharm., 249, 259-85. 



32 GENERAL METHODS AND CRUDE DRUG ASSAYS 

(2) Powdered cantharides is treated with a weighed amount of chloro- 
form in presence of hydrochloric acid, an aliquot is filtered, evaporated, 
the residue treated with petroleum ether for twenty-four hours, then 
washed with more petroleum ether, then with a very weak solu- 
tion of ammonium carbonate, and finally water; it is then dried at 
40° C. 

(3) The powder is treated with alcoholic hydrochloric acid for one- 
quarter hour and after evaporation of the acid, treated in a Soxhlet with 
a mixture of petroleum ether and benzol 3-5; the solvent is evaporated, 
the residue washed with a mixture of petroleum ether and alcohol 1-9 and 
dried at 60° C. 

The German Pharmacopoeia describes a method for the assay of can- 
tharides, the essentials of which are the same as the second manipula- 
tion above mentioned. The purification is, however, carried to greater 
length; after washing with ammonium carbonate the residue, which is 
still resinous or dark in color, is extracted with hot acetone which removes 
the cantharidin. 

The Assay of Cantharides (Leger.) 1 — Into a wide mouth flask which 
can be closed with a pledget of cotton place 25 grams of powdered can- 
tharides, 125 mils benzol, and 2 mils of HC1. Close the flask and keep 
at 60° or 65° in an oven for three hours with occasional agitation. Let 
cool and turn the contents of the flask into a displacement apparatus 
or into a percolator. Close below with cotton, wet with benzol and col- 
lect the issuing liquid into a flask and set this fraction (1) aside. Con- 
tinue the percolation to exhaustion, receiving the product (2) in another 
flask. The benzol extracts are distilled on a water-bath, beginning with 
fraction (2) and using a tared flask. When distillation ceases the last 
traces of benzol are removed by a current of air through the warm flask. 
After cooling add to the residue in the flask consisting of a green oil in 
which float crystals of cantharidin, 10 mils of petroleum ether which dis- 
tills entirely below 50°. Plug the flask and let stand twelve hours. Decant 
the liquid upon a 7-cm. filter paper which has been tared after drying 
at 60° or 65° C. and previously moistened with benzol. Retain the crystals 
as much as possible in the flask, wash them with 24 mils petroleum ether 
in four portions, which in turn being poured upon a filter is finally thoro- 
oughly washed with petroleum ether; dry in the air a few monents and 
then place both filter and flask in an oven at 60° or 65°, keeping the flask 
inclined. Weigh at the end of one hour. The amount of cantharidin 
should not be less than 40 per cent. The use of petroleum ether of low 
boiling-point permits the drying of the cantharidin at a temperature of 
60° or 65°, which minimizes the loss by volatilization. Moreover it is 
important to incline the flask while in the oven so as to facilitate the cir- 
iSchweiz. Wochenschr., 1903, 374; Jour, de Phar. et Chim., 1903, 457. 



CRUDE DRUG ASSAYS 33 

dilation of the gases in its interior. Finally the time in the stove is limited 
to one hour, which is sufficient for desiccation. 

CARDIAC STIMULANT DRUGS 

The drugs falling under this designation inciude Apocynum, Conval- 
laria, Digitalis, Squills, .Strophanthus and Epinephrin (Adrenalin.) Their 
physiological activity is best ■ ascertained by means of biochemic tests, 
which, in many instances, require special apparatus and knowledge of 
pharmacological technique. The Pharmacopoeia method of assaying 
Digitalis, Squills and Strophanthus has been described under " Digi- 
talis," and for the details of other methods the reader is referred to 
" Biochemic Drug Assay Methods " by P. S. Pittenger. 

Convallaria and Apocynum can be assayed by the Digitalis method, 
but the characteristic effects of Epinephrin and products of the supra- 
renal glands are best observed by the change in blood pressure due to 
intravenous injections, 

CINCHONA 

Cinchona bark is assayed for its content of total alkaloids, ether sol- 
uble alkaloids, and approximate amount of quinin. The ether soluble 
alkaloids are usually stated to consist of quinin, quinidin, and cinchonidin, 
but the figures reported often mean but little, as there are other basic 
substances in cinchona which dissolve in ether and the temperature at 
which the ether extraction is made, determines the amount of material 
dissolved. It has been the experience of the author that when using 
ether it was possible by varying the temperature of extraction to obtain 
almost any percentage up to that of total alkaloids. 

U. S. P., Ninth Revision Method. — The new method differs materi- 
ally from that in the 8th revision; no attempt is made to distinguish 
between total and ether-soluble alkaloids, and while the previous method 
depended on total extraction, which was by no means complete, the new 
assay is an aliquot process. 

Introduce 5 grams of Cinchona, in No. 40 powder, into a 500-mil flask 
and add 200 mils of a mixture of chloroform, 1 volume, and ether, 2 vol- 
umes. Stopper the flask, shake it well, and let it stand ten minutes. Then 
add 5 mils of ammonia water, shake the flask frequently for one hour, 
and let it stand from eight to ten hours. Now add 10 mils of distilled 
water, shake the mixture vigorously, and when the drug has settled, 
decant 160 mils of the solution, representing 4 grams of Cinchona. Filter 
it through a pledget of purified cotton into a separator, and rinse both 
cylinder and cotton with ether. Completely extract the alkaloids from 
the chloroform-ether solution by shaking out repeatedly with weak sul- 



34 GENERAL METHODS AND CRUDE DRUG ASSAYS 

phuric acid. Collect the acid solutions in a separator, add ammonia 
water until the solution is distinctly alkaline to litmus, and completely 
extract the alkaloids by shaking out repeatedly with chloroform. Filter 
each portion of chloroform as it comes from the separator through a pled- 
get of purified cotton into a tared flask, and wash the funnel and cotton 
with chloroform. Evaporate the chloroform on a water-bath, add 5 mils 
of alcohol to the residue, and again evaporate. Repeat the evaporation 
with alcohol and dry the residue at 100° C. to constant weight. The 
weight will be the amount of total alkaloids from 4 grams of Cinchona. 

A modification of Keller's method, made by Fromme, and improved 
by Engelhardt and Jones 1 is as follows: 2.5 grams of fine or moderately 
coarse powder are heated in a 200-mil flask with 2 mils of 25 per cent 
hydrochloric acid and 20 mils of distilled water for ten minutes on a steam 
bath; the flask is allowed to cool, and then 50 grams of ether and 25 grams 
of chloroform are added. The mixture is well shaken, supersaturated 
with 5 mils of caustic potash solution (15 per cent) and then shaken con- 
tinuously for fifteen minutes; 1.5 grams of gum tragacanth are now added 
and the mixture shaken again. After the liquids have separated, 60 grams 
(equal to 2 grams of bark) are filtered, and extracted three times with 
1 per cent hydrochloric acid, using 20, 10, and 10 mils respectively. The 
combined acid solutions are shaken well with 15 mils of chloroform, super- 
saturated with ammonia, and again well shaken. After settling, the 
chloroform is filtered through a double filter into a tared Erlenmeyer 
flask of 100 mils capacity, the aqueous solution shaken twice more with 
10 mils of chloroform, the additional chloroform filtered and added to 
the first. The solvent is then evaporated off and the residue dried at 
100° C. to a constant weight. The result is too high, owing to the pres- 
ence of fatty matter. The residue is therefore dissolved in 10 mils of 
alcohol and 10 mils of ether, when 30 mils of water are added; the solu- 
tion is colored with a few drops of hematoxylin solution, and N/10 sul- 
phuric acid added with constant shaking until the purple color has almost 
changed to yellow; 10 mils of water and more acid are now added until 
a lemon yellow is obtained; then 30 mils of water are added, and, after 
vigorous shaking, more acid is added until the lemon yellow color per- 
sists. Each mil of acid corresponds to 0.0039 gram of total Cinchona 
alkaloids. The relation of the percentages of the four principal alkaloids 
of the drug is almost constant. 

For the determination of the actual quinin in a bark, Duncan 2 has 
shown that sodium sulphate will salt out the quinin sulphate from the 
mixed alkaloids if the solution is kept below 30° C. for twenty-four hours. 
The quinin should be present in the proportion of .1 gram to 100 mils. 
The sulphuric acid solution of the mixed alkaloids is exactly neutralized 
iPharm. J., 1910, 84, 236. 2 Pharm. J., 1909, 82, 429-30. 



CRUDE DRUG ASSAYS 35 

with sodium hydroxide solution and 10 grams sodium sulphate added per 
100 mils. After twenty-four hours the quinin sulphate is filtered off 
and either washed with water saturated with quinin sulphate dried and 
weighed, or with alcohol containing 10 per cent sodium sulphate and 
titrated with N/20 alcoholic sodium hydroxide using phenolphthalein. 

Cohen 1 claims that by the above procedure pure quinin sulphate is 
not precipitated, and that even after purifying by a second precipitation 
the losses are much greater than with pure quinin. But whatever the 
merits of the controversy, the process is of value in aiding the chemist 
to obtain at least a good approximation of the quinin value of a bark. 

COCA 

DeJong, 2 who has probably given more attention than anyone else 
to the study of coca assay during the past few years, perfected a method 
which was published in 1908; 12.5 grams of finely powdered leaves are 
mixed with 5 mils of 25 per cent ammonia and the mixture extracted in 
a Soxhlet apparatus with light petroleum for ten to fifteen hours. After 
transferring the extract to a stoppered funnel and washing out the flask 
with light petroleum, the leaves are extracted again for three hours and 
the light petroleum tested by shaking it with 2 or 3 mils of dilute hydro- 
chloric acid, the acid should not give a turbidity with ammonia. The 
alkaloidal extract is now shaken with 50 mils and then with 25 mils of 
dilute (0.5 per cent) hydrochloric acid. When an emulsion is formed, 
this is transferred to a flask and the liquids separated by a current of air. 
The acid solution is then filtered through a small filter previously washed 
twice with water. The filtrate is shaken once with ether (which is set 
aside) and rendered alkaline with ammonia. It is then shaken first with 
50 and then with 25 mils of ether, the ethereal solution allowed to stand 
for a few minutes, transferred to a tared flask (care being taken not to 
pour in any drops of water), the flask washed twice with a few mils of 
ether, which are added to the bulk, the solution evaporated, and the 
flask heated several times in boiling water; after each heating a current 
of air is passed through. The flask is finally dried in a desiccator and 
weighed. 

Bierling, Pape, and Vierhover 3 made an exhaustive study of all the 
known methods of coca assay and conclude that the following procedures 
give the most reliable results: 10 grams of the air-dried, powdered leaves 
of known moisture content, are mixed with 4-5 mils of 30 per cent am- 
monia, and extracted with ether in a Soxhlet apparatus for four to five 

iPharm. J., 1909, 82, 670. 

2 Rev. Trav. chim. Pays-Bas, 1908, 27, 419-21. 

3 Arch. Pharm., 1910, 248, 303-36. 



36 GENERAL METHODS AND CRUDE DRUG ASSAYS 

hours. A few drops of the ether flowing from the drug should then give 
no reaction with Mayer's reagent. Or, 12 grams of the powdered 
leaves in a similar condition are put into a 200-mil flask with 120 
grams of ether and 6 mils of 10 per cent, or 3-4 mils of 30 
per cent ammonia, and shaken vigorously and repeatedly for half 
an hour. The liquid is filtered till 100 grams of filtrate are obtained, 
care being taken' to avoid loss by evaporation. The ethereal extract, 
obtained by either method, is shaken successively with 30, 10, and 10 
mils of 2 per cent hydrochloric acid. The last extract should give no 
reaction with Mayer's reagent. The acid extracts are filtered if neces- 
sary, and shaken out once with ether, if colored yellow. The extract 
is made alkaline with ammonia, and shaken with 40-50 mils of either till 
the aqueous portion is colorless or no longer turbid. The aqueous liquid 
is shaken twice more with 20 mils of ether. The ethereal solution is 
placed in a tared flask and the ether distilled off. The residue after being 
treated twice with 5 mils of ether, which is driven off each time by means 
of a current of dry air, is dried at 100° C. till of constant weight. It is 
dissolved in a little ether, treated with 5 mils of N/10 hydrochloric acid, 
and warmed to remove the ether. The excess of acid may then be titrated 
with caustic soda, after the addition of 10 drops of a fresh 1 per cent 
hsematoxylin solution and 40-50 mils of water, or after the addition of 
5 drops of iodeosin solution and some ether. If preferred the alkaloidal 
residue can be dissolved in 3-5 mils of absolute alcohol and titrated with 
N/10 hydrochloric acid, using two drops of 0.5 per cent methyl red as 
indicator. 

1 mil N/10 acid = 30.318 mg. cocain 

COLCHICUM 

Dohme, Engelhardt and Schmidt 1 have shown that the colchicin 
obtained in the assay of the corm by the U. S. P. Method, 8th revision, 
is 35-48 per cent pure and the seed 58-75 per cent. The old assay was 
replete with faults and was foreordained to give erroneous results. 

The new method for assaying Colchicum seed is as follows : Introduce 
15 grams of Colchicum Seed, in No. 60 powder, into a 500-mil flask, and 
add 10 mils of solution of lead subacetate and 290 mils of distilled water. 
Weigh the flask and contents, and digest the mixture at from 60° to 70° C. 
for three hours, with occasional agitation. Cool, add distilled water to 
restore the original weight, and filter off 200 mils. Add 0.75 gram of 
sodium phosphate to the clear filtrate, shake the mixture frequently dur- 
ing half an hour, and filter off 100 mils, representing 5 grams of Colchicum 
seed. Shake out the alkaloid from the filtrate with chloroform until com- 

1 Druggists' Circular, 1910, 58. 



CRUDE DRUG ASSAYS 37 

pletely extracted, as shown by testing with iodine T. S. (in place of the 
usual mercuric potassium iodid T. S.), and evaporate the chloroform solu- 
tion; add about one mil of alcohol and again evaporate. Repeat this 
operation once more and dry the residue to constant weight at 100° C. 
To this weighed residue contained in a flask add 5 mils of N/10 sulphuric 
acid V. S. and .5 mils of distilled water and heat the mixture for ten minutes 
at 70° C. Now filter the liquid through a pledget of purified cotton, 
wash the flask and cotton with distilled water, reject the filtrate and wash- 
ings and remove as much of the water from the cotton as possible. Dis- 
solve any insoluble residue that may remain on the cotton by washing 
it first with a little alcohol and then with ether; collect the alcohol-ether 
washings in the flask, evaporate, and dry the residue to constant weight 
at 100° C. Deduct this weight from the weight of residue previously 
obtained. The difference will be the weight of colchicin obtained from 
5 grams of Colchicum seed. 

There have been many methods proposed for the analysis of Colchicum, 
but all have failed to give a pure colchicin. Farr and Wright 1 seem to 
have made the greatest advance by recommending the purification of the 
crude colchicin with iodine and their method as a whole is especially 
commendable. Five grams of the powdered drug are packed in a perco- 
lator of 2 cm. diameter and exhausted by slow percolation with 50 per 
cent alcohol. The percolate is evaporated in a porcelain dish with 25 
mils water on the water-bath till the volume is reduced to 20 mils. The 
warm liquid is transferred to a separator and the dish rinsed with a little 
water and 25 mils of light petroleum ether. The aqueous solution is 
shaken with 20, 10, and 5 mils chloroform, the extraction being repeated 
as long as any alkaloid is extracted. The chloroform is distilled off and 
the residue treated with a mixture of 19 mils water and 1 mil ammonia, 
used in four portions, then with a mixture of 16 mils water and 4 mils 
dilute sulphuric acid. These solutions are now all filtered into a flask, 
the acid being in excess, 20 mils of iodine test solution added and the 
precipitate filtered off. The flask and precipitate are washed out with 
20 mils of water containing 1 mil each of sulphuric acid and iodine (as 
the alkaloidal iodides are unstable in the presence of water it would be 
safer to wash out the flask with test solution alone). The filter and con- 
tents are ground to a pulp with 20 mils sodium thiosulphate and 2 mils 
sodium carbonate test solutions, the mixture filtered through cotton into 
a separator, and the solid matter washed with water until it gives no pre- 
cipitate with iodine. The nitrate and washings are shaken out with 
chloroform, the solvent evaporated at a low temperature and the residue 
dissolved in 90 per cent alcohol, evaporated, and dried to constant weight 
at 100° C. 

1 Pharm. J., 1910, 85, 578-80. 



38 GENERAL METHODS AND CRUDE DRUG ASSAYS 

CONIUM 

National Formulary Method. — Place 15 grams of Conium, in No. 40 
powder, in a 250- mil Erlenmeyer flask, add 150 mils of purified petroleum 
benzin and then 15 mils of solution of sodium hydroxide, insert the stop- 
per securely, and shake the flask vigorously at frequent intervals during 
six hours. Allow the mixture to settle and decant 100 mils of the clear 
benzin solution (representing 10 grams of the drug) into a separator; 
extract the alkaloid by shaking with successive portions of weak hydro- 
chloric acid until a few drops of the last washing gives no precipitate 
with iodine T. S. Collect the acid washings and concentrate by evapora- 
tion on a water-bath to 10 mils, cool and transfer the liquid to a separator, 
then cautiously add sodium carbonate in excess. Extract the alkaloid 
by shaking out with successive portions of 15 mils each of purified petro- 
leum benzin. Separate the benzin washings and filter into a beaker. 
Then add exactly 10 mils of N/10 sulphuric acid V. S. and stir thoroughly 
for two minutes so as to mix the acid and benzin solution. Evaporate 
the benzin layer in a current of warm air, at a temperature not exceed- 
ing 60° C, and as soon as the benzin has disappeared, cool, add 5 drops 
of cochineal T. S. or methyl red T. S. and titrate the acid solution with 
N/50 potassium hydroxide V. S. Each mil of N/10 sulphuric acid V. S. 
consumed corresponds to 0.0126 gram of coniin. Calculate the amount 
of coniin neutralized by the acid, and multiply the result by ten to obtain 
the percentage of coniin in the drug. 

Squires method for the assay of conium and its preparations is as 
follows: 5 grams of the finely powdered drug or its equivalent of fluid 
extract or tincture evaporated on sawdust is extracted with 50 mils of 
chloroform saturated with hydrogen chloride, the extraction with a smaller 
quantity of the solvent being repeated until 6 drops on evaporation give 
no precipitate with Mayer's reagent and dilute-sulphuric acid. The total 
chloroformic extract is shaken out twice with 25-mil portions of water, 
and the latter washed twice with 10-mil portions of chloroform, which 
is discarded. The aqueous solution is made alkaline with sodium hydrox- 
ide and the coniin shaken out with 3 portions of chloroform; to the 
latter is added 10 mils of chloroform saturated with hydrogen chloride 
and the whole evaporated, dried at 90° C. and weighed; 162.4 parts of 
anhydrous coniin hydrochloride equals 126.2 parts of coniin. 

A simple volumetric titration method consists in treating 10 grams of 
the finely powdered drug or 10 mils of the fluid extract with 50 mils petro- 
leum ether and 5 mils of hydrochloric acid 10 per cent and thoroughly 
shaking. This operation is repeated, and then the drug is treated with 
80 mils of petroleum ether and sufficient potassium carbonate to render 
the mixture alkaline. After a thorough shaking the mixture is allowed 



CRUDE DRUG ASSAYS 39 

to stand overnight. Forty mils are then filtered into a titration flask, 
10 mils N/10 sulphuric acid are added, the petroleum ether evaporated 
at a gentle heat, and the excess of acid titrated with N/50 alkali. 

1 mil N/50 H 2 S0 4 = . 002543 gram coniin. 

DIGITALIS 

With Digitalis as well as with other drugs of the heart-tonic class the 
physiological assay seems to be the best measure of its therapeutic activity. 
The assays in general use include the minimum lethal dose method; Focke's 
method where the potency is assumed to be directly proportional to the 
weight of the frog and inversely to the dose and time, the value of the 
preparation being determined by the equation V = pdt; and the deter- 
mination of the amount of digitoxin by chemical means. Each physi- 
ological method has its own ardent supporters, and there is much con- 
troversy as to which is the best, but there are so many factors entering 
into animal experimentation that no attempt will be made to offer any 
opinion as to which method is the best. 

Schmiedeberg 1 has emphasized the unreliability of all methods for 
determining the activity of digitalis, and concludes that the relative activ- 
ity of different lots of leaves can be determined with sufficient accuracy 
as follows: the heart of Rana temporaria is exposed and connected with 
the Williams' frog heart apparatus and perfused with 2 parts 0.7 per cent 
sodium chloride solution and 1 part ox blood, to which the substance is 
added. The time is noted from the beginning of the poisoning till the 
cessation of the heart beats. Care must be taken that all the tests are 
made under as nearly identical conditions as possible, by the use of the 
same concentration of the leaf infusion, maintenance of constant con- 
centration during perfusion, and the employment of healthy male hearts. 
The infusion is made by 70 mils boiling water on 1 gram powdered leaves, 
shaking for five minutes, filtering and washing with hot water to a vol- 
ume of 100 mils; 95 per cent of the active principles are removed in this 
manner. The activity of the extracts of each lot is compared with that 
of strophanthin. It was found that there was no direct way of comparing 
the activity of any one extract with that of strophanthin, as only those 
quantities could be compared that produced the same effect in the same 
time. But the value of the extract can be compared with the activity 
of a certain amount of strophanthin calculated by interpolation in a series 
of results obtained with different amounts of strophanthin and so the 
extracts of several lots of leaves can be compared with one another. 

^rch. exp. path. Pharm., 62, 305-28. 



40 GENERAL METHODS AND CRUDE DRUG ASSAYS 

Physiological methods for Assay of Digitalis 

U. S. P., Ninth Revision. — After the frogs have been weighed, the doses 
to be given are calculated according to their weights and are measured 
into small conical glasses by means of a finely graduated pipette. The 
doses of the preparation which are to be injected should be as uniform 
in quantity as possible and should not exceed 0.015 mil for each gram 
of body weight of frog. The members of the digitalis series may be assayed 
in either fluid extract or tincture strength, being diluted with water as 
may be necessary to get the volume dose. In case the alcohol content 
in any preparation after dilution is higher than 20 per cent the prepara- 
tion may be subjected to careful evaporation and subsequent dilution 
with an aqueous solution containing 0.7 per cent of sodium chloride until 
the original volume is restored and the alcohol content is not above the 
per cent named. It is always best to have the alcohol content of different 
preparations uniform. In case there is a precipitate the preparation to 
be assayed should be shaken each time a dose is measured out. 

When the doses are ready, they may be injected into the anterior lymph 
sac of the animal. This is done by means of a glass pipette which is 
drawn out to a fine point. The frog is held on its back in one hand and. 
the pipette with the contained drug in the other, the mouth of the frog 
is opened with the point of the pipette and, carefully avoiding the tongue, 
the floor of the mouth is punctured and the point of the pipette is then 
seen to enter the anterior lymph sac of the frog. The contents of the 
pipette are now forced into the sac either by gravity or by gently blowing 
if necessary. In the latter case, care should be taken not to introduce 
air into the sac. Care should also be taken not to puncture the skin. 
The animal is then replaced in its cage in the tank, the temperature of 
which is maintained as stated at 20° C. 

At the end of one hour from the time of injection each frog is pithed, 
both brain and cord, the heart is exposed and its condition examined. 
For the correct end reaction the ventricle should be in systolic standstill 
while the auricles should be widely dilated. 

Following mechanical stimulation feeble contractions may be allowed 
in the auricles and localized contractions in the ventricle, but no general 
contraction is allowable. 

If when the heart of an animal is being exposed for examination, 
remains of the injected drug are found in the lymph sac unabsorbed, such 
an animal should be discarded and not considered in the results obtained. 

It happens sometimes that one frog out of a large series may prove 
a decided exception to the others in the way of increased or decreased 
susceptibility to the drug. Such an animal should also be discarded. 

After the primary or trial assay has been carried out and the approxi- 
mate strength of the preparation ascertained, a second series of frogs is 



CRUDE DRUG ASSAYS 41 

injected in like manner, using doses the limits of which are considerably 
narrower than the first series. A third or even fourth series of injections 
may be necessary to confirm the earlier results. The dose thus found 
is then compared with the dose of a standard which is similarly ascer- 
tained upon another series of frogs of the same lot. From such a com- 
parison the strength of the unknown preparation can be suitably adjusted. 
The use of a standard is made necessary by the fact that frogs differ 
in their susceptibility to the members of the digitalis series at different 
seasons of the year. The condition of susceptibility is ascertained and 
allowed for by the use of a solution of ouabain as a standard which in 
appropriate doses is injected into a series of frogs and their resistance 
thus determined. The necessary strength of an unknown preparation 
may be calculated from the dose actually found by the ratio of the stand- 
ard dose of ouabain to the dose of ouabain found necessary to kill. Thus: 

Standard dose . Found dose . . Standard dose . Necessary dose 
of ouabain of ouabain of drug being of unknown. 

assayed 

The standard dose of ouabain is 0.0000005 gram per gram of body 
weight of frog. 

The standard dose of Tincture of Digit ahs to correspond is 0.006 mil 
per gram of body weight of frog. 

If, therefore, in a certain series of frogs the resistance to ouabain is 
found to be increased so that a dose of 0.00000075 gram is necessaiy to 
stop the heart in systole in one hour, the dose of Tincture of Digitalis 
would also have to be increased to 0.009 mil, and the actual dose found 
calculated against this, instead of against the standard dose of 0.006 mil. 
For example, in frogs showing the increased resistance as indicated above 
if the Tincture being examined assays 0.018 mil per gram of body weight 
it is one-half strength. 

Standards. — The standards adopted are as follows: 

Gram or Mil for Each 

Gram of Body Weight 

of Frog. 

Standard dose of ouabain . 0000005 

Digitalis : 

Leaves fin the form of tincture) . 0006 

Fluid extract 0.0006 

Tincture : 0.006 

Strophanthus : 

Seed (in the form of tincture) 0.000006 

Tincture . 00006 

Squill: 

Dried Squill (in the form of tincture) . 0006 

Fluid extract 0.0006 

Tincture . 006 



42 GENERAL METHODS AND CRUDE DRUG ASSAYS 



KELLER'S METHOD FOR THE DETERMINATION OF DIGITOXIN 

Twenty-eight grams of air-dried, powdered digitalis leaves are placed in 
a suitable glass-stoppered flask of 500-mil capacity; over these are poured 
280 grams of alcohol 60 per cent (by weight) and the mixture is left to 
stand for three to four hours, shaking it frequently. It is then filtered 
and 207 grams of the filtrate are evaporated to about 25 grams on a water- 
ibath. Sufficient water is added to the residue to bring the total weight 
to 222 grams, and while stirring, 25 grams of official liq. plumbi subace- 
tatis fort, are added. The mixture is immediately filtered and to 132 
grams of the filtrate, in an Erlenmeyer flask, a solution of 5 grams of sodium 
sulphate in 8 grams of water is added. When the precipitate has settled, 
130 grams of the clear fluid are poured into a separator, 2 grams of solu- 
tion of ammonia (10 per cent NH3) are added and the mixture is shaken 
five times, each time with 30 mils of chloroform. The chloroformic solu- 
tions are filtered and then evaporated, the dry residue is dissolved in 3 
grams of chloroform, and, in order to precipitate the digitoxin, 7 grams 
of ether and 50 grams of petroleum ether are added. The flocculent 
digitoxin which separates is collected on a small filter (5 cm. diameter) 
and dissolved on the filter by the addition of hot absolute alcohol. The 
alcoholic solution which runs through is collected in a glass capsule, evap- 
orated to dryness and the residue dried until the weight is constant. This 
multiplied by 10 gives the percentage of digitoxin contained in the leaves 
analyzed. 

Vanderkleed 1 recommends a modification of Keller's method of chem- 
ical assay in which a determination of the digitoxin gives results in close 
accordance with the physiological determination of the lethal dose as 
shown by simultaneous control experiments. 

Twenty grams of the powdered leaves are extracted by percolation 
with 70 per cent alcohol, and the percolate is evaporated on the water- 
bath until all the alcohol has been driven off. In the case of the tinc- 
ture 200 mils, or a fluid extract, 20 mils, are similarly treated. The resi- 
due is rinsed with sufficient water to bring the volume to 150 mils. Fifteen 
mils of a 25 per cent solution of lead acetate are then added, and the 
mixture is diluted to 200 mils. The precipitate is filtered off, thoroughly 
drained and washed. The filtrate is made up to 200 mils and excess of 
lead removed by means of sodium sulphate or phosphate. After stand- 
ing for twenty-four hours, the precipitate is filtered off, drained, and 
washed. (The taking of aliquot parts, in order to avoid nitrations and 
washings, cannot be advocated in digitalis assays, on account of the 
volume of the precipitates.) The filtrate is transferred to a separator, 
2 mils pf 10 per cent solution of ammonia are added, and the alkaline 
*Amer. J. Pharm, 1908, 80, 114-20. 



CRUDE DRUG ASSAYS] 43 

liquid is shaken with five successive 30-mil portions of chloroform. The 
chloroform extract is distilled to dryness in a tared flask on the water- 
bath; the crude residual digitoxin is redissolved in 3 mils of chloroform; 
10 mils of ether and 70 mils of light petroleum spirit are added, and 
the mixture is allowed to stand in a cold place for twenty-four hours. 
The digitoxin, in a micro-crystalline form, adheres to the flask, allowing 
the greater part of the liquid to be decanted. The last few drops are 
evaporated, and the precipitate is dried, in the flask, at 60° C, and then 
weighed as digitoxin. The average amount of digitoxin found, in four 
years, in digitalis leaves is 0.313 per cent; the highest yield is 0.455 per 
cent; the lowest 0.171 per cent. Four samples of U. S. P. tincture gave 
from 0.023 to 0.037 per cent; one tincture free from fat yielded 0.027 
per cent. Three fluid extracts gave from 0.234 to 0.264 per cent, and the 
powdered solid extract 1.061 per cent of digitoxin. 

ERGOT 

Ergot may be assayed by several physiological methods including 
the cock's-comb method, the blood-pressure method, and uterine method. 
The latter two require special complicated apparatus and can be handled 
to advantage only by one skilled in pharmacological practice. The details 
of the manipulations are ably described in Pittenger's work, " Biochemic 
Drug Assay Methods." For practical purposes the cocks'-comb method 
yields good results and is not difficult to carry out. It consists in deter- 
mining the minimum amount of solution of ergot necessary to cause the 
same degree of bluing in the cock's comb and wattles as that produced 
by a given amount of a standard preparation. The best subjects are white 
Leghorn roosters weighing 1200-1600 grams, and the injections are made 
deep into the breast muscle, or the preparation to be tested may be intro- 
duced into the crop through a soft rubber tube. Pittenger's directions 
are as follows: 

Inject one cock with a dose of the standard preparation. Inject 
another with the same dose of the unknown preparation, and, one hour 
after the injections have been given, compare the color of the two combs, 
as the maximum cyanosis seems to be reached in about that time. The 
color begins to fade soon after, so that at the end of two hours or more, 
depending on the amount of drug given, the comb will usually appear 
to be nearly normal. Judging from the results obtained from the first 
two injections, the dose of the unknown preparation is increased or dimin- 
ished until that amount is found which will give approximately the 
same intensity of action as was shown by the color of the comb of the 
rooster injected with the standard. The same roosters may be used for 
several tests, but the injections should be made at intervals of two or 
three days, so as to allow sufficient time for complete recovery from the 



44 GENERAL METHODS AND CRUDE DRUG ASSAYS 

effects of previous administrations of the drug. It should be considered 
sufficiently accurate if the first injections of the standard and of the 
unknown preparations produce the same degree of activity, because it is 
believed that individual variation in different birds might be sufficiently 
great to interfere. This variation can be reduced to a minimum, if the 
order of the injection on the succeeding day be reversed until each prepara- 
tion has been given to each of several birds in turn. The results are 
then based on the average of the several injections. The final compari- 
sons demand careful selection of the birds to be injected. A choice of 
two birds of about the same size and which had previously reacted well 
to the drug is advisable. With a little practice it is easy to compare 
the intensity of the discoloration in the two cocks' combs and to so regu- 
late the dose of the drug given as to produce approximately the same 
degree of reaction. The doses thus obtained will give the relative strength 
of the two drugs. 

Variations may further be avoided by using only such roosters as react 
alike to a standard preparation, and also by constantly changing the order 
of injections so that the same cock shall not receive the same specimen 
of the drug twice in succession. Although the relative strength of two 
preparations may be thus determined quite accurately by this method, 
it is not well adapted for standardization work, because it requires that 
a standard preparation shall be kept on hand. This makes the standard 
dependent upon the keeping qualities of a stock galenical. Any deteri- 
oration, therefore, will result in a lowering of the standard for all sub- 
sequent preparations. Owing to the rapid deterioration in preparations 
of ergot, it is, therefore, practically impossible to keep on hand a prepara- 
tion of standard strength, and it is believed that more satisfactory results 
may be obtained by the blood-pressure method because the blood-pres- 
sure may be accurately measured by the manometer and kymograph and 
the same permanently recorded. The principal objection to this method, 
however, is the fact that the personal equation plays an important part 
in the assay, since the accuracy of the test depends largely upon the experi- 
ence of the operator and his ability in determining just when the color- 
ation produced by the unknown equals that produced by the standard. 
In the hands of an experienced operator, however, results may be obtained 
which will show, with fair accuracy, the relative value of any preparation 
of ergot. 

Standard fluid extracts should be prepared from good quality ergot. 
These standard products will keep without deterioration if preserved in 
sealed tubes from which the air has been exhausted. A standard extract 
will produce a moderate grade of cyanosis in doses of about 1 mil. 

Keller-Fromme Method for Determining Cornutin (Ergotinin) in 
Ergot. — Place 25 grams of finely powdered ergot in a small percolator 



CRUDE DRUG ASSAYS 45 

closed with a plug of cotton-wool, and slowly extract with petroleum ether 
until a drop on evaporation does not leave any oily stain on filter paper. 
The whole of the powder is then removed from the percolator and the 
petroleum ether allowed to evaporate off before introducing the powder 
into a bottle with a capacity of about 250 mils. Ether (125 mils) and 
magnesia mixture (1 gram of light magnesia and 40 grams of water) are 
then added, and the mixture shaken repeatedly during thirty minutes. 
Next 3 grams of powdered tragacanth are added, and the mixture well 
shaken prior to passing 100 grams (or as much as possible) of the ethereal 
solvent through a plug of cotton-wool in a covered funnel. The liquid 
(of which each 5 grams represents 1 gram of powder) is next shaken out 
with 25, 20, and 15 mils of dilute hydrochloric acid (1 per cent) until 
the acid liquor gives no cloudiness with Mayer's reagent. The bulked 
acid liquors are shaken up with 0.3 gram of kieselguhr and again filtered, 
washing the bottle and filter with a little water. The filtrate is then 
made alkaline with ammonia and shaken out with 25, 10, and 10 mils 
of ether, the ethereal solution being filtered into a tared Erlenmeyer flask. 
The solvent is removed by distillation and the residue dried till of con- 
stant weight. If 100 grams of ether solution were shaken out, this weight, 
multiplied by 5, is equal to the percentage of cornutin (ergotinin.) 

GELSEMIUM 

A simple process consists in treating 20 grams of the powdered drug 
or 20 mils of the fluid extract evaporated on sawdust, with 150 mils ether 
and 4 mils ammonia water and thoroughly shaking. Seventy-five mils 
of the clear liquid are then transferred to a separator and extracted with 
5 per cent sulphuric acid, the latter being filtered into another separator 
and shaken out once with petroleum ether, which is discarded. Ammonia 
is added in excess and the alkaline liquid shaken out with ether-chloro- 
form 3-1, the latter being filtered into a tared dish, evaporated, dried, 
and weighed. 

Sayre 1 recommends Webster's process, by which 10 mils of the fluid 
extract are precipitated with 1.5 grams tartaric acid, filtered, and the 
precipitate washed with alcohol, the filtrate and washings made up to 
100 mils and allowed to stand until any further precipitate has settled, 
and again filtered. One-half of the filtrate (representing 5 mils) is evap- 
orated to dryness and the residue treated with 10 mils N/2 sulphuric acid 
and filtered into a separator; potassium hydroxide 20 per cent is added in 
excess and the alkaloids shaken out with chloroform-ether (4-1); the 
solvent is washed with two portions of water and treated with 20 mils 
N/100 sulphuric acid, thoroughly shaken and the excess of acid titrated 
with N/100 alkali, using cochineal. 

1 mil N/100 H 2 S0 4 = .00408 gram Gelsemium Alkaloids. 
1 Drug. Circ, 1911, 55. 



46 GENERAL METHODS AND CRUDE DRUG ASSAYS 



GUARANA 

The new aliquot gravimetric method of the U. S. P., Ninth revision, 
does not give a caffein which can be termed strictly pure. Pure caffein 
residues cannot be obtained from any drug or caffein-containing sub- 
stance without an iodine purification. 

The method is as follows: Introduce 6 grams of Guarana in No. 60 
powder into a flask and add 120 mils chloroform and 6 mils ammonia 
water. Stopper the flask, shake it frequently for half an hour, then let 
it stand four hours. Again shake the flask vigorously and when the drug 
has settled decant 100 mils of the liquid representing 5 grams of Guarana, 
then filter through a pledget of purified cotton. Evaporate the clear 
filtrate to dryness and dissolve the residue in weak sulphuric acid with 
the aid of heat. When the liquid has cooled filter it into a separator and 
wash the container and filter with several small portions of distilled water. 
Now add ammonia water until the liquid is distinctly alkaline and com- 
pletely extract the caffein by repeatedly shaking out with chloroform. 
Evaporate the united chloroform solution to constant weight at 80° C. 
and weigh. 

HOANG-NAN AND IGNATIA 

These two drugs contain strychnin and brucin, and they and their 
extracts can be assayed by the same methods as obtain with mix vomica. 

HYDRASTIS 

U. S. P., Ninth Revision Method. — Introduce 10 grams of Hydrastis, 
in No. 60 powder, into a 250-mil flask and add 100 mils of ether and 
proceed as directed under " Belladonna," beginning with the word 
" Stopper." Modify the process there given by using 50 mils of the ether 
solution, representing 5 grams of Hydrastis, to complete the assay. Use 
ether instead of chloroform for the final shaking out of the alkaloids, and 
dry the residue to constant weight at 100° C. instead of titrating. The 
weight is the amount of ether-soluble alkaloids from 5 grams of Hydrastis. 

John Uri Lloyd's Method. — 

Very finely powdered Hydrastis (passed through fine bolting 

cloth) 2 grams 

Lloyd's reagent (see page 68) 1 gram 

Ammoniated alcohol (not ammonia water) . . 10 mils } . , 

Chloroform 100 mils J 

Glycerin 8 mils 

Aqua ammonia, q. s. 

Sulphuric ether 60 mils 

Into a stoppered, 8-oz. separator, put 50 mils of the chloroform-ammoni- 
ated alcohol mixture. Add the Hydrastis, and shake well together. Next 



CRUDE DRUG ASSAYS 47 

add the Lloyd's reagent, and shake well together. Then add the glycerin 
and shake vigorously, until perfect separation of the chloroformic liquid 
and the resultant magma takes place. Draw off the chloroform solution, 
filtering through a cottoned separator with 20 mils of the chloroform- 
ammonia solution, shaking vigorously, as before, and drawing off the 
clear solution, filtering through the same cottoned funnel as previously 
used, into the distilling flask. Repeat, with 20 mils of the chloroform- 
ammonia solution, until this is exhausted (three washings.) 

In the process above given, it is essential that no filter paper be em- 
ployed. Filter through pledget of cotton, previously saturated with the 
appropriate menstruum. (In this instance, chloroform.) 

Connect the flask with a condenser, and (water-bath) distill off the 
chloroform. The residue will not become dry, by reason of a small portion 
of glycerin. Wash this residue with diluted sulphuric acid (one-fourth 
the strength of U. S. P. dilute sulphuric acid), using three successive 
portions of 10 mils each, and filtering through a cottoned funnel (water- 
saturated), into an 8-oz. separator. Add ammonia water to slight excess, 
and abstract with 20 mils sulphuric ether, filtering the ether. Repeat, 
using two other portions of sulphuric ether, 20 mils each, and evaporate 
to dryness. Flow over the residue 5 mils cold, distilled water, and decant. 
This, to remove traces of ammonium sulphate. Dry the residue per- 
fectly, multiply by 100 and divide by 2. The result gives the percentage 
of pure hydrastin in the drug, in an amorphous form. If the crystalline 
form is desired, dissolve in a small amount of alcohol, and allow to evap- 
orate spontaneously. 

Roeder's 1 method, which is a type of several methods, proposed for 
determining hydrastin in the extract is as follows: 

Six grams of the fluid extract are diluted with about 5 mils of water, 
and evaporated to drive off the alcohol. After cooling, 2 mils of 20 per 
cent sulphuric acid are added, the mixture being allowed to stand, with 
occasional agitation, for from one-half to one hour. Twenty grams of 
light petroleum spirit and 100 grams of ether are added; after well shak- 
ing, sufficient 10 per cent solution of ammonia to give an alkaline reaction 
(about 5 mils) is run in, and the whole is well shaken for ten to fifteen 
minutes. After separation, a portion of the ether layer equivalent to 
5 grams of the original extract is decanted and shaken with 25, 25, 10, 
and 10 mils of 0.5 per cent hydrochloric acid, or until a drop of the acid 
liquid gives no reaction with Mayer's reagent. The united acid extract 
is filtered into a separator, the alkaloid is liberated with excess of ammonia, 
and extracted with 50, 30, 10, 10, and 10 mils of ether in succession. The 
ether solutions are evaporated in a tared vessel, and the residue dried at 
100° C, is weighed. In the case of the rhizome, 6 grams of the diug, 
l Apoth. Zeit., 1908, 23, 583. 



48 GENERAL METHODS AND CRUDE DRUG ASSAYS 

in finest powder, are extracted with ether, and the ether residue is treated 
as above. 

Rupp 1 describes a method which is representative of another type of 
assay : Ten grams of the liquid extract are mixed, in a tared 125-mil Erlen- 
meyer flask, with 20 grams of water, and evaporated by gentle boiling 
until the weight is reduced to 9 or 11 grams, in order to drive off the alcohol. 
After cooling somewhat, 1.5 grams of dilute hydrochloric acid are added, 
and the total weight is brought up to 20 grams by the addition of more 
water. One gram of talc is then added, the mixture is strongly shaken 
for one minute, and thrown on a plain filter. Ten grams of filtrate are 
collected in a 100-mil flask; 4 grams of solution of ammonia and 20 grams 
of ether are added and the whole is well shaken for a minute; 20 grams 
of light petroleum spirit are then added, and thorough agitation is repeated ; 
after a further addition of 1.5 grams of powdered tragacanth, the whole 
is shaken until the gum aggregates. Thirty-two grams of the clear liquid 
( = 4 grams of the original extract) are then decanted into a tall, tared 
beaker, the solvent is evaporated off, and the residue of hydrastin dried 
till of constant weight. 

HYOSCYAMUS 

The method in the ninth revision U. S. P. is the same as for Belladonna 
leaves except that 30 grams of drug in No. 60 powder and 300 c.c. of the 
chloroform-ether mixture are to be used. The amount of distilled water 
to be added after maceration is increased to 40 mils, and 200 mils of the 
chloroform-ether solution are taken, representing 20 grams of Hyoscyamus. 

IPECAC 

The method in the ninth revision U. S. P. is identical with that for 
Belladonna leaves, with the exception that 10 grams of the drug in No. 
80 powder, to 100 mils of ether are used, and 50 mils of the ether solution 
representing 5 grams of Ipecac taken. Ether only is used, throughout 
and the residue is dissolved in 10 mils of N/10 sulphuric acid. Each mil 
of the acid consumed corresponds to 24 milligrams of Ipecac alkaloids. 

Patterson 2 gives a method for estimating the emetin and cephaelin 
in Ipecac which he considers both simple and rapid. Twelve grams of 
the powdered drug are mixed with 10 mils ammonia water or 10 mils 
sodium carbonate (1-3) and 120 mils of a mixture of 1 part chloroform, 
1 part amyl alcohol, and 3 parts ether. The whole is well shaken for an 
hour, 10-15 mils water added to aggregate the powder, 100 mils of the 
liquid decanted and evaporated to one-half if ammonia has been used. 
It is then shaken out with 15 mils N/10 hydrochloric acid, followed by 
^poth. Zeit., 1909, 24, 922-923. 'Pharm. J., 1903, 71, 102. 



CRUDE DRUG ASSAYS 4$ 

three portions of water 5 mils each, the acid solution treated with excess 
of N/1 potassium hydroxide and shaken out four times with ether, pre- 
serving both aqueous and ethereal solutions. The latter are shaken out 
three times with N/20 potassium hydroxide, the potash solution washed 
once with ether and then all the ethereal solutions evaporated and weighed 
or titrated as emetin. The aqueous solutions are then mixed, acidified 
with hydrochloric acid, ammonia added in excess and shaken out four 
or five times with ether-chloroform (1-6), the latter evaporated and the 
residue weighed or titrated as cephaelin. 

JALAP 

The U. S. P., ninth revision directs as follows: Pack 10 grams of jalap 
in No 60 powder in a cylindrical percolator and extract it with alcohol 
until 100 mils of percolate is obtained. Transfer 20 mils of the percolate 
to a separator, add 20 mils of chloroform. Mix the liquids, then add 
20 mils of distilled water and shake throughly. When the liquids have 
completely separated, draw off the chloroform into a tared beaker, wash 
the separator with 5 mils chloroform and add it to the beaker. Evapor- 
ate the chloroform solution on a water-bath, add 2 mils of alcohol and 
again evaporate, dry to constant weight and weigh. The resulting weight 
will be the amount of total resin obtained. 

KOLA 

National Formulary Method. — Introduce 6 grams of Kola, in No. 60 
powder, into a flask and add 120 mils of chloroform and 6 mils of ammonia 
water. Stopper the flask, shake it frequently for half an hour, then let 
it stand four hours. Again shake the flask vigorously and, when the drug 
has settled, filter the liquid rapidly through a pledget of purified cotton 
and collect 100 mils of the nitrate, representing 5 grams of kola. Evapo- 
rate the clear nitrate to dryness and dissolve the resdue in 5 mils of weak 
sulphuric acid with the aid of a gentle heat. When the liquid has cooled, 
filter it into a separator and wash the container and filter with several 
small portions of distilled water. Now add ammonia water until the 
liquid is distinctly alkaline to litmus and shake out the alkaloid with 
successive portions of chloroform until completely extracted, as shown 
by testing with iodine T. S. Evaporate the united chloroform solutions 
and dry the residue to constant weight at 80° C. The weight is the 
amount of caffein from 5 grams of Kola. 

Kola yields not more than 3 per cent of ash. 

LICORICE 

Tschirch has shown that glycyrrhizin on hydrolysis yields two mole- 
cules of glucuronic acid, an aldehyde acid which reduces Fehling's solu- 



50 GENERAL METHODS AND CRUDE DRUG ASSAYS 

tion, and based on this fact Eriksson x has proposed a method for esti- 
mating glycyrrhizin both in the extract and the drug. Ten grams of 
the extract coarsely powdered are treated with 100 mils of cold water 
and when dissolved 100 mils of 90 per cent alcohol added, heated for one- 
half hour on the water-bath, filtered, the filter washed with 50 mils of 
hot alcohol, the nitrate heated on the water-bath until the alcohol is 
removed, and then made up to 200 mils with water. Forty mils of this 
solution are treated with 25 per cent sulphuric acid as long as a precipi- 
tate is formed, and after standing two to three hours, the glycyrrhizin 
is filtered off and washed with 5 per cent sulphuric acid. The filter with 
the glycyrrhizin is heated with 50 mils 90 per cent alcohol, filtered and 
30 mils water added to the filtrate. The alcohol is driven off and the 
glycyrrhizin is reprecipitated with sulphuric acid, filtered, dissolved in 
5 per cent sodium hydroxide, diluted with water, and boiled under a reflux 
for fifteen hours with 120 mils of Fehling's solution. The copper reduc- 
ing power of the solution is then determined in terms of dextrose and 
from the amount of the latter the glycyrrhizin is calculated, 360 parts 
of dextrose being equivalent to 896 parts of glycyrrhizin. 

The method may be applied to licorice root. The ground root is 
extracted with alkaline water, and after precipitating gummy substances 
with alcohol, the solution is boiled for three to five minutes with excess 
of Fehling's solution until the reduction due to reducing sugars and hexoses 
is complete and after filtering from the cuprous oxide, the glycyrrhizin is 
determined by boiling for fifteen hours with Fehling's solution. 

Glycyrrhizin may also be determined gravimetrically: two grams of 
the extract are dissolved in 30 mils of warm water and to the cool solu- 
tion 118 mils of 95 per cent alcohol added and the flask allowed to stand 
twelve hours. The precipitate is then filtered and washed with 75 per 
cent alcohol and the filtrate evaporated. The residue is dissolved in 
warm water and precipitated with 10 per cent sulphuric acid, the precipi- 
tate is washed with acidulated water and finally with a small quantity of 
distilled water cooled to 2° C, then dissolved in strong ammonia and the 
solution evaporated to dryness in a tared dish, dried at 100° C. and the 
residue weighed as ammonium glycyrrhizinate. 

LOBELIA 

Lobelin, the alkaloid of Lobelia inflata, may be determined in the 
tincture by Farr and Wright's method: Fifty mils of the tincture are 
treated with 5 drops of acetic acid 33 per cent and 20-30 mils of water 
and evaporated on the water-bath to about 30 mils. The liquid is filtered 
through cotton into a separator and the dish and cotton washed with 
1 Arch. Pharm., 1911, 249, 144-60. 



CRUDE DRUG ASSAYS 51 

acidified water. Ammonia is then added in excess and the liberated 
alkaloid shaken out three times with a little chloroform, the solvent is 
evaporated at a gentle heat, and the residue treated twice with 5 mils 
of hydrochloric acid 1 per cent, filtering into a separator. Ammonia is 
added in excess, and the liquid shaken out with 3 portions of anhydrous 
ether, the solvent evaporated, and the residue weighed after drying at 
100° C. 

The authors claim there is no loss on drying at 100° C. but, after 
driving off the ether the safer procedure would be to bring to a constant 
weight in a desiccator. 

MUSTARD SEED 

The German Pharmacopoeia contains a method for determining the 
allylisothiocyanate in mustard seed. The powdered seed is digested with 
water for two hours; alcohol and a little olive oil added, the mixture 
distilled and the distillate received in a flask containing ammonia. A 
known quantity of standard silver nitrate is then added and the mixture 
digested for an hour on the water-bath. An aliquot is filtered and the 
excess of silver determined by titrating with potassium thiocyanate. 

Each mil N/10 silver nitrate =.004956 gram allylisothiocyanate. 

Viehoever has proposed an improved method for determining the 
allylisothiocyanate. Five grams of the seed in No. 20 powder are placed 
in a 200-mil flask, 100 mils of water added, stoppered tightly and macer- 
ated at 37° C. for two hours. 

Then add 20 mils of alcohol (95 per. cent) and distill about 50 mils 
into a 100-mil volumetric flask containing 10 mils of alcohol (95 per cent) 
and 10 mils of ammonia water (10 per cent). (The mouth of the con- 
denser should extend below the surface of the liquid in the receiver.) 
Add 20 mils of N/10 silver nitrate to the distillate, set aside twenty- 
four hours, heat to boiling, cool, fill up to the mark, and filter. To 50 
mils of the clear filtrate add an excess of nitric acid (sp. gr. about 1.4) 
and 1 mil of ferric ammonium sulphate solution (10 per cent), and titrate 
with N/10 ammonium thiocyanate solution. 

State the results in the number of mils of N/10 silver nitrate consumed 
or in terms of allylisothiocyanate (each mil of N/10 silver nitrate con- 
sumed equals 0.004956 gram of allylisothiocyanate,) 

NUX VOMICA 

The method of the U. S. P. ninth revision is identical with that given 
for Belladonna, with the exception that the drug in No. 40 powder is used, 
10 mils ammonia added, and after shaking, the flask stands ten hours 



52 GENERAL METHODS AND CRUDE DRUG ASSAYS 

and is then treated with 25 mils distilled water, 10 mils of N/10 sulphuric 
acid is used in place of N/50 acid. Each mil of N/10 sulphuric acid cor- 
responds to 36.4 milligrams total alkaloids. 

The standard for Nux Vomica in the eighth revision was based on 
the content of strychnin and not on the total alkaloids, and the separa- 
tion was effected by means of nitric acid. 

The situation with respect to the assay of Nux Vomica is analogous 
to that obtaining in the case of aconite. The amount of total alkaloids 
is not necessarily a measure of the therapeutic activity of the drug. Dixon 
and Harvey 1 report that the relative toxicity of brucin to strychnin has 
been found to be as 4 : 33, and that the action is quite distinct from that 
of strychnin, more nearly approaching that of methyl strychnin. 

In view of this difference and since the proportions of the two alkaloids 
are by no means constant, all Nux Vomica preparations should be assayed 
for their strychnin content. In the eighth revision the alkaloidal resi- 
due was dissolved in dilute sulphuric acid, treated with nitric acid, and 
after standing the strychnin liberated with sodium hydroxide and shaken 
out with chloroform. This method has been criticised, but the author 
has found it very satisfactory and has used it to advantage in determin- 
ing the strychnin content of Nux Vomica. The details are as follows: 
dissolve the alkaloidal residue in 15 mils 3 per cent sulphuric acid, warm- 
ing on the water-bath. When cool add 3 mils of a cooled mixture of 
equal volumes nitric acid 1.42 sp. gr. and distilled water, and after rotat- 
ing the liquid a few 7 times set it aside for exactly ten minutes, shaking 
it gently three times during the interval. Transfer the resulting red 
liquid to a separator containing 25 mils of an aqueous solution of sodium 
hydroxide 1-10 and wash the flask three times with a very small amount 
of distilled water, and add the washings to the separator, if the liquid is 
not turbid add 2 mils more sodium hydroxide. Now add 20 mils of chloro- 
form and shake it well by a rotating motion for a few minutes, allow the 
liquids to separate, and draw off the chloroform through a small filter 
wetted with chloroform into a flask; repeat twice, using 10 mils chloro- 
form each time and draw off both portions into the flask using the same 
filter. Finally wash the filter and funnel with 5 mils chloroform and 
evaporate filtrate, weighing or titrating the residue as strychnin. 

Webster and Pursel 2 found that more definite and complete elimi- 
nation of the brucin is obtained by treating with nitric acid containing 
a little sodium nitrite in the presence of sulphuric acid. The separated 
alkaloids are dissolved in 15 mils of 3 per cent sulphuric acid, to this solu- 
tion are added 3 mils of a mixture of equal volumes of concentrated nitric 
acid and distilled water followed by 1 mil of a 5 per cent solution of sodium 
nitrite. After mixing, the liquid is allowed to stand for exactly thirty 
1 Pharm. J., 1908, 81, 367. 2 Amer. Drug., 1906, 50, 362-3. 



CRUDE DRUG ASSAYS 53 

minutes with occasional shaking. It is then made alkaline and the strych- 
nin shaken out with chloroform. 

The ferrocyanide method of separating strychnin and brucm also gives 
satisfaction in the hands of careful workers; to make this separation the 
mixed alkaloids obtained by the U. S. P. assay are dissolved in 15 mils 
of dilute sulphuric acid and diluted with 100 mils water; 25 mils of 5 per 
cent potassium ferrocyanide are then added, and the mixture well shaken 
and allowed to stand six hours. The precipitate is transferred to a small 
filter, washed with water containing about ^o its volume of dilute sul- 
phuric acid, rinsed into a separator, treated with 5 mils ammonia and 
shaken out with chloroform. The solvent is run through cotton wool and 
evaporated and the residue weighed as strychnin. 

Matthes and Rammstedt 1 have evolved a method of assay depend- 
ing on the precipitate formed with picrolonic acid. Fifteen grams of the 
powdered drug dried at 100° C. are treated with 100 grams ether and 50 
grams chloroform, and after a thorough shaking, 10 mils of dilute sodium- 
hydroxide added and the mixture agitated for ten minutes. Fifteen mils 
of water, or a sufficient quantity to cause the drug to aggregate when 
shaken, are added and the whole set aside until the solvent separates as 
a clear liquid; after thirty minutes 50 grams of the solution, represent- 
ing 5 grams of the drug, are filtered off, evaporated to one-half and 5 
mils of N/10 picrolonic acid (dinitrophenylmethyl pyrazolone) added to 
the warm liquid which is then set aside in a cool place for twenty-four 
hours. The precipitated strychnin-brucin picrolonate is collected in a 
tared Gooch, washed with 2 mils of ether-alcohol (3-1), dried for thirty 
minutes at 110° and weighed. The mean molecular weight of strychnin- 
brucin being 364.32 and that of the picrolonate 628.32, the weight of the 
latter obtained multiplied by 0.5798 gives the equivalent of mixed bases. 

OPIUM 

The assay of opium has been the subject of much study and probably 
more methods have been proposed than for any other drug. The valu- 
ation has always been based on its morphin content and the problem 
has been to separate this alkaloid from some twenty or more others. 
Nearly all the methods have depended upon the precipitation of morphin, 
which is then either weighed or titrated. Recently its separation by 
chloroform-alcohol mixture has been employed with considerable success. 

Taylor has given an exhaustive and comprehensive review of the 
methods of opium assay in the new edition of Allen. 

U. S. P., Ninth Revision. — Introduce 8 grams of Opium, which if fresh 
should be in very small pieces, and if dry in fine powder, into Erlenmeyer 
flask having a capacity of about 250 mils, add 80 mils of distilled water, 
1 Arch. PhaTm., 1907, 245, 112-32. 



54 GENERAL METHODS AND CRUDE DRUG ASSAYS 

stopper the flask, and agitate it every ten minutes (or continuously in 
a mechanical shaker) during three hours. Then pour the contents as evenly 
as possible upon a wetted filter having a diameter of not over 12 cm., 
and, when the liquid has drained off, wash the residue with distilled water 
carefully dropped upon the edges of the filter and its contents, until 120 
mils of filtrate have been obtained. Carefully transfer the moist Opium 
to a mortar by means of a spatula, and rub to a smooth paste, then rinse 
into the original flask with 50 mils of distilled water, agitate it thoroughly 
and return the whole to the filter. When the liquid has drained off, 
wash the residue with 75 mils of distilled water. Evaporate the mixed 
filtrates and washings on a water-bath to about 40 grams. Transfer the 
extract to a 50-mil graduated flask and wash the evaporating dish with 
sufficient distilled water to make the entire volume measure exactly 50 
mils when cooled to room temperature. Place in a small mortar 4 grams 
of freshly slaked lime, add about 10 mils of the opium extract and rub 
to a smooth paste, then add the remainder of the extract and rinse the 
flask with exactly 10 mils of distilled water, adding the rinsings to the 
mortar, and stir frequently during fifteen minutes, avoiding unnecessary 
loss by evaporation. Filter through a dry filter, about 10 cm. in diameter, 
and transfer exactly 30 mils of the filtrate, representing 4 grams of Opium, 
to an Erlenmeyer flask of suitable capacity. To this add 2 mils of alcohol 
and 15 mils of ether, and, after shaking the mixture, add 1 gram of ammo- 
nium chloride, stopper the flask and shake it frequently during half an 
hour, then set it aside in a cool place for twelve hours or overnight. 
Remove the stopper and brush any adhering crystals back into the flask. 
Decant the ethereal layer into a small funnel, the neck of which has been 
previously closed with a pledget of purified cotton. Rinse the flask and 
contents with 15 mils of ether, and, when the ether has passed through, 
wash the funnel and cotton with a small quantity of ether, and then pour 
the aqueous liquid into the funnel without trying to remove the crystals. 
Wash the crystals in the flask and the contents of the funnel with distilled 
water, previously saturated with morphin, until the washings are color- 
less. Then add a few drops of distilled water to replace the morphinated 
water. Incline the edge of the funnel over the mouth of the flask and 
by means of a glass rod carefully transfer the cotton with adhering crys- 
tals to the flask. Insert the funnel into the neck of the flask and wash 
the funnel with 20 mils of N/10 sulphuric acid V. S., followed by 10 mils 
of distilled water, applied drop by drop around the edge of the funnel. 
Remove the funnel, replace the cork, warm gently, and agitate until the 
crystals are dissolved. Rinse the cork with distilled water and titrate 
the excess of acid with N/50 potassium hydroxide V. S., cochineal T. S. 
being used as indicator. Each mil of N/10 sulphuric acid V. S. consumed 
corresponds to 0.028516 gram of anhydrous morphin. 



CRUDE DRUG ASSAYS . 55 

U. S. P., Eighth Revision. — Introduce 10 gr«ams Opium (which, if 
fresh, should be in very small pieces, and if dry, in very fine powder) 
into an Erlenmeyer flask having a capacity of about 300 mils, add 100 
mils of distilled water, stopper the flask, and agitate it every ten minutes 
(or continuously in a mechanical shaker) during three hours. Then pour 
the contents as evenly as possible upon a wetted filter having a diameter 
of 12 cm., and, when the liquid has drained off, wash the residue with 
distilled water, carefully dropped upon the edges of the filter and its con- 
tents, until 150 mils of filtrate have been obtained. Then carefully trans- 
fer the moist Opium back to the flask by means of a spatula, add 50 mils 
of distilled water, agitate it thoroughly and repeatedly during fifteen min- 
utes, and return the whole to the filter. When the liquid has drained off, 
wash the residue, as before, until the second filtrate measures 150 mils, 
and finally collect about 20 mils more of a third filtrate. Evaporate care- 
fully in a tared dish, first, the second filtrate to a small volume, then add 
the first filtrate, rinsing the vessels with the third filtrate, and continue 
the evaporation until the residue weighs 14 grams. Rotate the concen- 
trated solution about in the dish until the rings of extract are redissolved, 
pour the liquid into a tared Erlenmeyer flask having a capacity of about 
100 mils, and rinse the dish with a few drops of water at a time until the 
entire solution, after the rinsings have been added to the flask, weighs 20 
grams. Then add 10 grams (or 12.2 mils) of alcohol, shake the flask well, 
add 25 mils of ether . and repeat the shaking. Now add 3.5 mils of am- 
monia water from a graduated pipette or burette, stopper the flask with 
a sound cork, shake it thoroughly during ten minutes, and then set it 
aside, in a moderately cool place, for at least sixteen hours. 

Remove the stopper carefully, and should any crystals adhere to it, 
brush them into the flask. Place in a small funnel two rapidly acting 
filters, of a diameter of 7 cm., plainly folded, one within the other (the 
triple fold of the inner filter being laid against the single side of the outer 
filter), wet them well with ether, and decant the ethereal solution as com- 
pletely as possible upon the inner filter. Add 10 mils of ether to the 
contents of the flask, rotate it, and again decant the ethereal layer upon 
the inner filter. Repeat this operation with another portion of 10 mils 
of ether. Then pour the liquid in the flask into the filter, in portions, 
in such a way as to transfer the greater portion of the crystals to the 
filter, and when the liquid has passed through, transfer the remaining 
crystals to the filter by washing the flask with several portions of water, 
using not more than 15 mils in all. Use a feather or rubber-tipped glass 
rod to remove the crystals that adhere to the flask. Allow the double 
filter to drain, then apply water to the crystals, drop by drop, until they 
are practically free from mother-liquor, and afterwards wash them, drop 
by drop, from a pipette, with alcohol previously saturated with powdered 



56 GENERAL METHODS AND CRUDE DRUG ASSAYS 

morphin. When this has passed through, displace the remaining alcohol 
by ether, using about 10 mils or more, if necessary. Allow the filter 
to dry in a moderately warm place, at a temperature not exceeding 60° 
C. (140° F.) until its weight remains constant, then carefully transfer 
the crystals to a tared watch-glass and weigh them. 

Place the crystals (which are not quite pure) in an Erlenmeyer flask, 
add lime water (10 mils for each 0.1 gram of morphin) and shake the 
flask at intervals during half an hour. Pass the liquid through two coun- 
terpoised rapidly acting plainly folded filters, one within the other (the 
triple fold of the inner filter being laid against the single fold of the outer 
filter), rinse the flask with more lime water and pass the washings through 
the filter until the filtrate, after acidulating, no longer yields a precipi- 
tate with mercuric potassium iodine T. S. Press the filters until nearly 
dry between bibulous paper and dry them to a constant weight, then weigh 
the contents, using the outer filter as a counterpoise. Deduct the weight 
of the insoluble matter on the filter from the weight of the impure mor- 
phin previously found. The difference, multiplied by 10, represents the 
percentage of crystallized morphin contained in the Opium. 

Stevens' Method. — Take 8 grams of dried and finely powdered opium 
and triturate in a mortar with 4 grams of fresh oxide of lime (not air slaked) 
and 20 mils of water until a uniform mixture results. Add 38 mils of 
water and stir frequently for half an hour. Filter through a dry 10-cm. 
filter and transfer exactly 30 mils to a 120-mil flask. To this add 8 mils 
of alcohol and 20 mils of ether and shake the mixture. Add 1.0 gram 
ammonium chloride, shake well and frequently for half an hour and set 
aside in a cool place for twelve hours. 

Remove the stopper carefully and preserve, with any adhering crys- 
tals, for future use. Pour the ethereal layer into a small funnel, the neck 
of which has been previously closed with a piece of absorbent cotton. 
Rinse the bottle with 20 mils of ether, and when this has passed through, 
pour the contents of the bottle into the funnel. Without trying to remove 
all the crystals from the bottle, wash the bottle and contents of the funnel 
with morphinated water until the washings are colorless. When the 
crystals have drained, place the funnel in the bottle containing adhering 
crystals, and with a small glass rod drawn out to a curved point, lift the 
cotton and rinse the crystals into the bottle with 25 mils of N/10 sulphuric 
acid, using the cotton on the end of the rod to detach any adhering crys- 
tals. Place the cotton in the bottle, replace the cork and agitate until 
the crystals are all dissolved. Rinse the cork and funnel with water and 
titrate the excess of acid with N/10 potassium hydroxide. 

The number of mils of N/10 acid consumed by the morphin, multi- 
plied by 1.516, will give the percentage of crystallized morphin obtained. 
To this add 1.12 for the morphin remaining in the solution. 



CRUDE DRUG ASSAYS 57 

Eaton's Method. — Place 1 gram of the dried and powdered sample 
in a suitable flask, add 100 mils of limewater (U. S. P.) from a pipette, 
stopper, and shake thoroughly every ten minutes, or continuously on the 
mechanical shaker, during two hours. Allow to settle, filter rapidly 
through a dry fluted filter. Remove 50 mils of the clear filtrate and trans- 
fer to a separatory funnel (No. 1). Shake out seven times with washed 
chloroform (chloroform washed with water), using 30 mils each time; col- 
lect the chloroform in a separatory funnel (No. 2) . Shake out once more 
with chloroform, transfer this chloroform into another separatory funnel 
(No. 3), containing 15 mils of clear limewater. Shake up funnel No. 3, 
withdraw the chloroform, filter, if necessary, and evaporate to dryness. 
Moisten the residue with a few drops of dilute acid, then add 1 drop of 
Mayer's reagent. If there is a precipitate, repeat this process of shaking 
out the original solution with chloroform, washing the chloroform with 
limewater in funnel No. 3, evaporating, and testing as indicated above, 
until Mayer's reagent gives a negative test. Now add the limewater in 
funnel No. 3 to the chloroform in funnel No. 2, shake thoroughly, reject 
the chloroform, wash the limewater with 30 mils of chloroform, again 
reject the chloroform and add the limewater to the original solution in 
funnel No. 1. Add lj to 2 mils of a 10 per cent solution of ammonium 
chloride; or else, neutralize closely with acid, then add ammonia by drops, 
using no more than 3 or 4 drops in excess. Shake out seven times with 
a mixture of chloroform and alcohol (2 parts of chloroform to 1 part of 
alcohol by volume), using 30 mils each time and collecting the chloro- 
form-alcohol in a separatory funnel. Shake out once more with chloro- 
form-alcohol, take about 5 mils of the last shake-out, evaporate to dry- 
ness, moisten with a few drops of dilute acid and test with Mayer's reagent. 
If there is a precipitate, repeat extraction and subsequent testing on a 
portion until Mayer's reagent gives a negative test. Combine the chloro- 
form-alcohol shake-outs, wash once or twice with 10 mils of water, then 
in turn wash the water twice with an equal volume of chloroform-alcohol. 
Filter and wash. Evaporate the chloroform-alcohol to dryness (on the 
steam-bath), dissolve the residue in 10 mils of warm neutral alcohol, add 
a convenient excess of N/50 sulphuric acid, evaporate most of the alcohol, 
and titrate back with N/50 potassium or sodium hydroxid, using cochineal 
(U. S. P. 5 drops) or methyl red (A per cent in alcoholic solution 3 
drops), as indicator. If methyl red is used the alcohol need not be evapor- 
ated; instead, dilute with about 10 or 15 mils of water before titrating 
back with alkali. Subtract the number of mils of alkali from the number of 
mils of acid used. One mil of acid corresponds to 6 milligrams of morphin. 

Debourdeaux 1 has shown that there is a variable portion of the 
morphin in opium which cannot be extracted by water alone. He com- 
1 J. Pharm. Chim., 1911, 4, 13-18, 65-69, 105-112. 



58 GENERAL METHODS AND CRUDE DRUG ASSAYS 

pared the methods of the German, Belgian, Swiss, United States, English, 
and French pharmacopoeias and from the results of the investigation 
concluded that the following methods are the best. 

Total Morphin. — Fifteen grams of opium passed through a No. 100 
sieve, are triturated with 6 grams of slaked lime of the same fineness. 
The mixture is diluted with water to 171 grams, agitated frequently for 
two hours and then filtered; 104 mils or 105.5 grams of the filtrate are 
shaken first with 10 mils of 95 per cent alcohol, and then with 50 mils 
ether, 2 grams ammonium chloride are added, and after further agitation 
to dissolve the salt, the whole is left for twenty-four hours for the morphin 
to crystallize. The ether is decanted off through a tared Gooch crucible, 
and the residue is treated with a further 10 mils of ether which is then 
also passed through the Gooch. The remaining solution with the morphin 
is now poured into the crucible, which is washed with 6 portions of 5 mils 
of water saturated with morphin and ether. The washing is continued 
if necessary until the ammonium chloride is completely removed. The 
crucible, with the morphin is dried at 100° C., washed with 5 portions of 
100 mils each of crystallizable benzol, again dried at 100° C. and weighed. 

Soluble Morphin. — Eighteen grams of opium passed through a No. 
100 sieve are treated with 144 grams of water, and after agitating two 
hours the mixture is filtered; 127 grams of the filtrate are triturated 
with 5.3 grams of slaked lime, and water added until the total weight 
is 162 grams. After one hour, with agitation, the mixture is filtered and 
104 mils, or 105.5 grams, of the filtrate are treated as described above. 

Hilton's 1 Modification of the U. S. P., Eighth Method for Opium Prep- 
arations. — Transfer 100 mils of tincture of opium or other liquid opium 
preparation to an evaporating dish and evaporate it on a water-bath to 
about 20 mils, add 40 mils of distilled water, mix thoroughly and set the 
liquid aside for one hour, occasionally stirring to disintegrate the resinous 
flakes adhering to the dish. Having set up a 25-mil Gooch crucible and 
prepared a matrix of asbestos by pouring some of the solution suspended 
in water in the crucible, after starting the filter pump, wash the matrix 
with alcohol and ignite the crucible; when cold, connect the crucible, 
after emptying the filter flask and rinsing the same with distilled water, 
pour carefully the contents of the dish into the crucible after starting 
the filter pump, when all of the liquid has passed through, disconnect 
the flask and reserve the filtrate for the final evaporation. Connect the 
flask again and wash the mass on the filter until completely exhausted 
(indicated by almost a colorless filtrate and the absence of bitterness). 
Evaporate the washings in a tared dish to a small volume, then add the 
first filtrate, rinsing the vessel with several small portions of distilled 
water and evaporate the whole to a weight of 14 grams. 
1 Jour. Amer. Pharm. Assn., 1912. 



CRUDE DRUG ASSAYS 59 

Proceed as directed under Opium, U. S. P. VIII, beginning "rotate 
the concentrated solution about in the dish until the rings of extract 
are redissolved," etc. After standing six hours or overnight as 
directed, proceed as follows: 

Having set up the Gooch crucible, prepare the matrix as previously 
indicated, wash with alcohol and ignite, cool in the desiccator and weigh, 
noting the weight of the crucible. Remove the stopper carefully from 
the flask, and should any crystals adhere to it, brush them into the flask. 
Wet the matrix in the crucible well with ether, and decant the ethereal 
solution in the flask as completely as possible upon the matrix in the 
crucible, after starting the filter pump. Add 10 mils of ether to the flask 
and proceed as directed in the U. S. P. VIII, using the Gooch crucible 
for the purpose of collecting and washing the morphine crystals, as therein 
directed. When this has been completed, remove the Gooch crucible and 
dry same in the oven at a moderate temperature not exceeding 60° C. 
(140° F.), until the weight of the crucible and its contents remains con- 
stant. Note the weight and deduct the weight of the crucible previously 
obtained. This gives the weight of the impure Morphin. 

Replace the Gooch crucible and pass lime water through the crucible 
(10 mils for each 0.1 gram of Morphin), reducing the vacuum in the filter 
flask so that the limewater comes through slowly, dissolving out the mor- 
phin, then wash the crucible with more limewater until after acidulation, 
the washings no longer yield a precipitate with mercuric potassium iodide, 
disconnect the crucible and dry in the oven ar a temperature of 100° C. 
(212° F.) to a constant weight, deduct the weight of the crucible; this 
gives the weight of the insoluble matter in the crucible to be deducted 
from the weight of the impure morphin previously obtained, this difference 
represents the percentage of crystallized morphin in 100 mils of the 
tincture or liquid preparation assayed. 

DETERMINATION OF MORPHIN IN TINCTURE OF OPIUM 

Evaporate the solution to drive off the alcohol, and if the prepara- 
tion contains much extracted matter make up to about 25 mils of water 
and add a slight excess of lead acetate solution. Filter into a 100-mil 
graduated flask, wash with a little water and to the filtrate add dry sodium 
phosphate in excess. Make up to the mark with water, filter off 25-mil 
portions, place in separator and add a slight excess of 10 per cent KOH. 
Shake out three times with chloroform, collecting chloroformic extracts 
in the second separator. Wash the chloroform with distilled water, dis- 
card chloroform, and run wash water into alkaline liquid. Then shake 
out four times with 15-mil portions of a mixture of chloroform and alcohol 
2 to 1. Separate and evaporate the solvent. The residue will contain 
any morphin originally present. Dissolve this residue in dilute sulphuric 



60 GENERAL METHODS AND CRUDE DRUG ASSAYS 

acid, pour into separator, shake out with 15 mils chloroform. Collect 
chloroform in a second separator, wash once with water, discard chloro- 
form, run wash water into acid liquid, add a slight excess dilute KOH and 
extract with chloroform and then with chloroform-alcohol mixture exactly 
as in the first instance. Finally run the solvent through absorbent cotton 
loosely stuck into the stem of the separator into an evaporating dish or 
beaker. The residue may then be titrated for morphin by dissolving 
in N/10 or N/50 H2SO4 and titrating back with N/50 NaOH, 

PHYSOSTIGMA 

U. S. P., Ninth Revision Method. — Introduce 15 grams of Physostigma 
in No. 60 powder, into a flask of about 250 mils capacity, and add 150 
mils of ether. Stopper the flask, shake it well and allow it to stand ten 
minutes, then add 10 mils of an aqueous solution of sodium bicarbonate 
(1 in 20) and shake the mixture vigorously at intervals during four hours. 
Now add 15 mils of distilled water, again shake the flask well, and, when 
the drug has settled, decant 100 mils of the ether solution, representing 
10 grams of Physostigma. Filter the solution through a pledget of puri- 
fied cotton into a beaker and rinse the graduate and cotton with ether. 
Add 20 mils of N/10 sulphuric acid V. S. and evaporate off the ether, 
stirring during the evaporation with a rubber-tipped glass rod. After the 
resinous and fatty matter has agglutinated, pour off the acid solution 
through a wetted filter into a separator. Redissolve the residue in the 
beaker in about 15 mils of ether, add 2 mils of N/10 sulphuric acid V. S., 
evaporate off the the ether with continued stirring as before and pour 
the acid solution on the filter. Repeat this operation until all of the 
alkaloid is extracted and then wash the filter with distilled water until 
it is free from alkaloids. Collect the solutions and washings in a separator, 
add sufficient sodium bicarbonate to make the solution decidedly alkaline 
to litmus and completely extract the alkaloids by shaking it out repeatedly 
with ether. Wash the combined ether solutions with 10 mils of distilled 
water, separate the water completely, and filter the ether solutions, wash- 
ing the container and filter with ether. Evaporate the ether solution to 
dryness, dissolve the alkaloids from the residue in exactly 5 mils of N/10 
sulphuric acid V. S. and titrate the excess of acid with N/50 potassium 
hydroxide V. S., using cochineal T. S. as indicator. 

Each mil of N/10 sulphuric acid V. S. consumed corresponds to 27.52 
milligrams of the alkaloids of Phvsostigma. 

PILOCARPUS 

U. S. P., Ninth Revision Method. — Introduce 15 grams of Pilocarpus 
in No. 60 powder into a 250-mil flask, add 150 mils of chloroform and 



CRUDE DRUG ASSAYS 61 

proceed as directed under " Belladonna/ ' third line of the assay, 
beginning with the word " Stopper/' and decreasing the amount of water 
to be added after maceration to 5 mils. The 100 mils of chloroform 
solution must be drawn off from the bottom of the flask, and dissolve 
the alkaloids from the residue in 8 mils of N/10 sulphuric acid V. S. 

Each mil of N/10 sulphuric acid V. S. corresponds to 20.8 milligrams 
of the alkaloids of Pilocarpus. 

A simple method consists in shaking 20 grams of the powdered drug, 
or 20 mils of the fluid extract, evaporated on sawdust, with 150 mils of 
Prolius mixture (ether 4, chloroform 1, alcohol 1) and 4 mils ammonia 
water; filtering off 75 mils of the clear liquid into a separator and exhaust- 
ing with 5 per cent nitric acid. The acid solution is then shaken once with 
chloroform which is discarded, and then made alkaline with ammonia and 
shaken out with chloroform, the solvent being filtered through a pledget 
of cotton into a tared dish, evaporated, dried and weighed. 

Matthes and Rammstedt 1 have applied their picrolonic acid method 
to Pilocarpus: fifteen grams of the moderately finely powdered drug are 
macerated for thirty minutes with 150 grams chloroform and 10 grams 
ammonia water; 100 grams of the solvent (representing 10 grams of drug) 
are then filtered off and evaporated to 20 mils; 3 mils N/10 picrolonic 
acid and 60 mils ether are added, the mixture set aside for twenty-four 
hours and the precipitate collected on a tared Gooch crucible, washed 
with 2 mils ether-alcohol 3-1, dried and weighed. The molecular weight 
of pilocarpin picrolonate is 472. 

POMEGRANATE BARK 

Method of the German Pharmacopoeia. — To determine total alkaloids, 
pour 90 grams of ether and 30 grams of chloroform upon 12 grams of 
rather finely ground pomegranate bark, dried at 100° C. and placed in 
an Erlenmeyer flask. Shake vigorously and add 10 mils of a mixture of 
2 parts of sodium hydroxide solution and 1 part of water. Let the mix- 
ture stand three hours, shake vigorously at frequent intervals. Then add 
10 mils of water, which will cause the powder to gather into balls after 
vigorous shaking, and leave the supernatant ether-chloroform solution 
perfectly clear. After an hour, pass 100 grams of the clear ether-chloro- 
form solution through a diy filter, kept well covered and receive the fil- 
trate in a separating funnel. Extract this nitrate with 50 mils of N/10 
hydrochloric acid and pass this acid solution, when perfectly clear, through 
a small filter moistened with water into a 100-mil flask. Make three more 
extractions with 10-mil portions of water, and pass these extractions 
through the same filter. Wash the filter with water and dilute the total 
1 Arch. Pharm., 1907, 245, 112-32. 



62 GENERAL METHODS AND CRUDE DRUG ASSAYS 

solution with water to 100 mils. Place 50 mils of this solution in a 200- 
mil flask with 50 mils of water and enough ether to make a layer about 
1 cm. thick. Add 5 drops of iodeosine solution and titrate with N/10 
potassium hydroxide solution, shaking vigorously after each addition, 
to give a pale red color to the lower aqueous solution. 

1 mil N/100 HC1 = .00147 gram mixed alkaloids. 

RHUBARB 

Tschirch and Edner 1 recommend the use of diazotized paranitranilin 
for determining the value of rhubarb. The reagent is thus prepared: 
Five grams of paranitranilin are treated with 25 mils of water and 6 
mils of strong sulphuric acid; after agitation, another 100 mils of water 
and a solution of 3 grams of sodium nitrite in 25 mils of water are added; 
the whole is then made up to 500 mils with water. The reagent should 
be protected from the light. From 0.5 to 1.0 gram of powdered rhubarb 
is boiled with successive quantities of dilute alcoholic potassium hydrox- 
ide solution until thoroughly extracted. The bulked filtered solutions 
are then distilled, and the alcohol-free residue diluted with water; the 
solution is then acidified with hydrochloric acid, and the precipitate formed 
on standing is collected, washed with acidified water, and dried. The dry 
filter and precipitate are then extracted with boiling chloroform for sev- 
eral hours in a Soxhlet apparatus; this removes only the hydroxymethyl- 
anthraquinones, leaving rheotannic acid insoluble. The chloroform is 
distilled off, and the residue dissolved by heating with 10 mils of 5 per 
cent sodium hydroxide solution and diluted with 50 mils of water. Twenty 
mils of diazotized paranitranilin solution are then added, and hydro- 
chloric acid, drop by drop, with thorough agitation, until the color of 
the solution is discharged and an acid reaction obtained. After stand- 
ing for a few hours, the precipitate formed is collected on a tared filter, 
washed free from acid, dried at 70° C, and weighed. The weight of 
hydroxymethylanthraquinones obtained is conveniently expressed in terms 
of chrysophanol (chrysophanic acid), the molecular weight of the chryso- 
phanolazo-compound being 447 and of that body itself 254; the ratio 
being, therefore, in round numbers, 4.5 : 2.5. The reaction may be 
expressed by the following equation, taking chrysophanol as the example: 

C 6 H 4 (N0 2 )N : NCl+Ci5Hs0 2 (OH)2+3NaOH 

= ((C 6 H 4 (N0 2 )N : NCi 5 H 7 2 (ONa) 2 )) + NaCl+3H 2 0. 
iArch. Phar. 1907,245, 150. 



CRUDE DRUG ASSAYS 63 

SABADILLA SEED 

T. Ryden 1 gives a method for determining the alkaloidal content of 
this drug. Ten grams of the powdered sample are shaken one half-hour 
with 100 mils ether, 10 mils 10 per cent ammonia water are added and 
the mixture shaken for two hours. The ether is filtered through cotton 
and 50 mils are concentrated to 10-15 mils. The ethereal solution is 
shaken out first with 15 mils N/1 hydrochloric acid and then with suc- 
cessive portions of 10 mils water until a drop of the acid solution gives 
no reaction with Mayer's reagent. The whole of the acid solution is 
made alkaline with sodium carbonate solution 33 per cent and extracted 
with 25, 10, and 10 mils of ether, repeating until a drop of the ethereal 
extract on evaporation gives no reaction with Mayer's reagent. The 
ethereal extract is evaporated, dried, and weighed or titrated with N/10 
acid, 1 mil of which is equivalent to 0.05984 gram of alkaloid. 

SANGUINARIA 

Fluid Extract. — The assay of the fluid extract is most readily accom- 
plished in the following manner: 

Take 10 mils of fluid extract of Sanguinaria, run into acidulated (acetic 
acid) water; and make up to 250 mils. Filter, and take duplicate por- 
tions of 100 mils each, equal to 4 mils of fluid extract. Place the clear 
red filtrate in a separatory funnel, make alkaline with ammonia, and 
shake out with chloroform, using 15, 10, 10, and 5 mils successively. A 
purple coloring matter is removed along with the alkaloid, but it does 
not interfere with the assay, as is the case with the methods heretofore 
in vogue. Run the chloroform into a small dish or beaker, and evapor- 
ate with gentle heat, or allow to evaporate spontaneously. 

The residue of alkaloids and coloring matter is of a resinous consistency, 
and is not readily soluble in diluted acetic acid, so that solution is best 
effected by adding 1 or 2 mils of chloroform to dissolve, then running in 
20 to 30 mils of N/50 sulphuric acid, and warming on the water-bath 
until the chloroform is all expelled. The solution of the alkaloid is now 
washed into a measuring flask and cooled. Mayer's reagent is added to 
complete precipitation, and the whole is made up to definite volume (50 
or 100 mils) with water. This is then filtered, and the excess of acid 
titrated with N/50 KOH, using phenolphthalein as an indicator. 

Since the average of the molecular weights is very close to the molec- 
ular weight of chelerythrine, we are justified in assuming that we are 
estimating pure chelerythrine. 

Now calculate the quantity of acid removed with the alkaloid, and 
1 Apoth. Zeit., 1912, 27-104. 



64 GENERAL METHODS AND CRUDE DRUG ASSAYS 

from that determine the quantity of alkaloid present. One mil of N/50 
acid is equal to .006943 gram Chelerythrin. 

Solid Extract. — In the case of an extract made with alcohol, a weighed 
portion is placed in a flask with about 10 parts of 70 per cent alcohol, 
acidulated (acetic acid), and warmed until it is dissolved, after which 
the procedure is exactly as above. 

If the extract is an aqueous one, it can be dissolved at once in acidu- 
lated water, made alkaline v/ith ammonia, and shaken out with chloro- 
form as above. 

Under conditions not yet well understood, heat destroys the alkaloids 
more or less completely, and it is therefore necessary to avoid the use of 
heat so far as possible in all manipulations of the drug. 

Crude Drug. — For the assay of the crude drug, 5 grams of the powder 
are moistened with ammonia water, carefully dried, and extracted with 
chloroform in a Soxhlet apparatus. The chloroform is then expelled from 
the percolate and the residue treated exactly as in the case of the fluid 
and solid extracts. 

A simple method of assay of Sanguinaria consists in shaking 5 grams 
of the powdered drug with 150 mils ether and 4 mils ammonia water, 
filtering 75 mils of the clear liquid into a separator and extracting with 
10 per cent acetic acid. The acid solution is filtered into another sepa- 
rator, washed once with petroleum ether which is discarded, and then 
made alkaline with ammonia, and the alkaloid removed with ether-petro- 
leum ether 2-1. The solvent is filtered into a tared dish, washing filter 
carefully, evaporated, dried at 100° C. and weighed. 

Schlotterbeck's method modified for the fluid extract is as follows: 
Five mils of the extract are treated with 10 mils of water, and 4 mils of 
ammonia, and shaken out with two successive portions of 15 mils ether; 
the aqueous layer is then treated with 10 mils alcohol and exhausted with 
ether; the combined ether solutions are then evaporated and the residue 
dissolved in 2 mils chlorofrom. Ten mils of water and 5 mils of N/20 
sulphuric acid are added and the chloroform evaporated, the acid solu- 
tion is stirred and filtered, and the gummy residue extracted twice with 
acid water, using 3 and 2 mils of the N/10 acid. The alkaloid is then 
precipitated with excess of Mayer's reagent, the mixture shaken and 
made up to 100 mils with water, 50 mils filtered off, decolorized with 
sodium thiosulphate and the excess of acid titrated with N/50 potassium 
hydroxide. 

The factor is .035. 

SANTONICA 

Several methods have been proposed for estimating Santonin, and 
the experiences of reputable chemists with these methods has been most 



CRUDE DRUG ASSAYS 65 

interesting. Caspari, working with the methods of Katz and Thaeter, 
was unable to get concordant results, or, in fact, any information about 
the drug which he considered reliable; he prefers Fromme's method, 
which he claims yielded accurate and reliable data. Nelson found the 
Katz method satisfactory and, after slight modifications, submitted it 
to the Association of Official Agricultural Chemists for trial, and the 
results were concordant. The author has found the Xelson-Katz method 
easy to handle and apparently capable of yielding accurate results, and 
has been unable to confirm Caspari's results with the Fromme method. 
In view of the uncertain situation all methods will be given. 

K. Thaeter 1 gives the following process: For the quantitative deter- 
mination of santonin, 10 grams of the powdered drug are extracted with 
ether for twelve hours in a Soxhlet tube; the extract, after the evapor- 
ation of the ether, is heated for an hour with 5 grams of caustic lime and 
about 300 mils of water, then filtered and washed with water. The result- 
ing filtrate is acidified with sulphuric acid, warmed until crystals of 
santonin are formed, when 100 grams of the official solution of aluminium 
acetate of the German Pharmacopoeia are added. The liquid is then 
evaporated to dryness, the residue is powdered, mixed with 3 grams of 
magnesium oxide, again moistened with water, dried, and finally, after 
drying at 105° C, extracted with anhydrous, acid-free ether for five hours. 
In this manner the total santonin present is extracted, and may be obtained, 
on the evaporation of the solvent, in pure condition for weighing. 

Katz 2 Method. — Ten grams of the coarsely powdered wormwood seeds 
are extracted with ether for two hours in a Soxhlet apparatus, and after 
distilling off the ether, the residue is boiled for twenty minutes with a 
5 per cent solution of barium hydrate under an inverted condenser. The 
solution is then cooled and saturated with carbonic acid, filtered quickly, 
and the residue washed twice with 20 mils of water. The filtrate is evap- 
orated on the water-bath to about 20 mils, then treated with 10 mils of 
12.5 per cent hydrochloric acid, left two minutes more on the water-bath 
and then cooled. The product is placed in a separating cylinder, and 
shaken with about 20 mils of chloroform, which dissolves the santonin. 
The chloroform solution is filtered and evaporated, and the residue is 
boiled with 50 mils of 15 per cent alcohol for ten minutes under an inverted 
condenser, the solution is filtered hot into a weighed flask, and allowed 
to stand for twenty-four hours. The alcohol is poured off from the sepa- 
rated santonin through a weighed filter, which is then dried along with 
the crystallized santonin, and weighed. A correction of 0.006 gram per 
10 mils of filtrate must be made for the solubility of santonin in the 
alcohol. 
The method of Fromme is as follows: Thirteen grams of moderately 
1 Arch, der Pharm., 236 (5) 383. 2 Arch. Pharm,. 1899, 237-245 



66 GENERAL METHODS AND CRUDE DRUG ASSAYS 

finely powdered wormseed are placed in a separatory funnel containing 
130 grams of chloroform. A pledget of cotton should be placed in the 
separatory above the stopcock before introducing the wormseed. After 
one hour maceration with occasional shaking, 102.5 grams, equal to 10 
grams of drug, of the liquid are drawn off into a 200-mil Erlenmeyer 
flask. Evaporate the chloroform until the residue weighs 7 to 8 grams. 
Add 100 grams of 5 per cent barium hydroxide solution and place the 
flask in hot water. After the chloroform has evaporated sufficiently to 
enable the resin to rise to the surface, it is heated until all odor of chloro- 
form has disappeared. Filter through a plain filter of 6 cm. diameter, 
previously wetted, into a 200-mil Erlenmeyer flask; rinse the flask and 
filter twice with 10 mils of hot water, add 5 grams of 25 per cent hydro- 
chloric acid to the filtrate and heat the whole for several minutes on a 
boiling-water bath. After the liquid has been cooled somewhat by set- 
ting the flask in cold water, pour the liquid into a separatory funnel and 
rinse the flask with 20 mils of chloroform, which is added to the contents 
of the separatory. Shake the mixture actively for two minutes and after 
the chloroform has separated perfectly, filter the same through a double 
plain filter into a 100-mil Erlenmeyer flask. Wash the acid aqueous 
liquid twice with 15 mils of chloroform by agitation and draw the chloro- 
form off as before through the filter. Distill the chloroform from the 
combined filtrate and remove the last traces of chloroform from the resi- 
due by a current of warm air. Dissolve the residue in 7.5 grams of abso- 
lute alcohol and add 42.5 grams of hot distilled water. Filter the milky 
liquid at once into a tared 100-mil Erlenmeyer flask and wash the flask 
and filter twice with 10 grams of a mixture of 3 grams of absolute alcohol 
and 17 grams of distilled water. Set the filtrate aside for twenty-four 
hours (not longer) and filter through a plain 6 cm. tared filter, washing 
the flask and filter twice with 10 grams of the above alcohol-water mix- 
ture. Dry the flask and filter at 100° C. to constant weight, place in a 
desiccator for one-half hour and weigh again. To the weight, of the 
santonin thus found add 0.04 gram for loss by solution in the dilute alco- 
hol. The total weight of santonin multiplied by 10, gives the percentage 
content, which should be calculated on the basis of previously dried 
wormseed. 

The Determination of Santonin in Santonica (Levant Wormseed.) — 
E. K. Nelson. — Extract 10 grams of medium-ground Levant Wormseed 
in a Soxhlet extraction apparatus for three hours with chloroform. Dis- 
till off the chloroform till 7-8 grams remain, add 100 grams 5 per cent 
solution of barium hydroxide, and heat on the steam-bath till the odor of 
chloroform has disappeared. Boil for five minutes, cool and pass CO2 
(which has been washed through sodium bicarbonate solution to free it from 
traces of acid which might be carried over mechanically) till saturated. 



CRUDE DRUG ASSAYS 67 

An excess of CO2 was found to do no harm. Filter by suction, best on 
a small Buchner funnel, and wash twice with 10 mils 25 per cent HC1 and 
warm five minutes. Cool till lukewarm and extract with 20, 15, 15 mils 
chloroform, passing the solvent through a small filter into a flask. Evapor- 
ate to dryness, being careful to see that the last traces of chloroform are 
removed. Add 7.5 grams of absolute alcohol to the residue, and dissolve 
(by gentle warming if necessary.) Then add 42.5 grams of water heated 
to 60-70°, stopper the flask and allow to cool. (Right here it is advis- 
able to see that crystallization starts, which can be done by scratching 
the side with a minute crystal of santonin. Samples put aside in a cool 
place for twenty-four hours, and which contain santonin in liberal amount 
have been found in a" supersaturated condition where this precaution was 
not observed.) Place the flask in a temperature of 15-17° for twenty- 
four hours. (Refrigerator compartment away from the ice.) Filter and 
wash with two portions of 10 mils 15 per cent (by wt.) alcohol. Dry 
flask and filter at 100°, dissolve santonin left in flask in chloroform 
and filter into a tared beaker. Wash santonin out of flask and filter 
thoroughly with chloroform, evaporate filtrate and dry at 100° till all 
traces of chloroform are gone. To the weight found add 0.04 gram for 
the santonin dissolved in the dilute alcohol, and multiply the total by 10 
for the per cent santonin. 

(The solubility factor was found correct for a temperature of 15-17°. 
At 30-32°, ,054 gram santonin was left in solution.) 

STRAMONIUM 

The method of the U. S. P., ninth revision, is identical with that given 
for Belladonna, using 15 grams of drug in No. 60 powder, increasing 
the amount of water to be added after maceration to 25 mils, and, before 
titration, treating the final residue twice with 5 mils of ether, evapor- 
ating each time. 

STROPHANTHUS 

J. Haycock 1 first percolates the powdered drug with petroleum ether 
to remove the oil, then dries and exhausts with 70 per cent alcohol. The 
alcoholic extract is evaporated to a soft extract at a low temperature, 
dissolved in 100 mils of water, 2 mils of 25 per cent sulphuric acid added 
and the liquid shaken three times with 20 mils of ether. The aqueous 
portion is heated to 75° C. for one hour. When cold the strophanthidin 
formed by the heating, is shaken out with chloroform, the solvent evapor- 
ated, a little alcohol added, dried at 65° C. and weighed. The result 
divided by 0.365 gives the amount of strophanthin present, 
^rit. & Co. Druggist, 1911, 59, 94. 



68 GENERAL METHODS AND CRUDE DRUG ASSAYS 

Physiological Assay. — A physiological assay probably furnishes the 
best measure of the therapeutic value of Strophanthus, and the procedure 
is the same as that described under " Digitalis." 

VERATRUM 

The literature on the subject of assaying Veratrum is meager, but a 
determination of the total alkaloids is not difficult. 

Bredemann 1 gives a method for the determination of the total alkaloids 
in Veratrum album: Twelve grams of the powdered drug are treated 
with 120 mils ether-chloroform 1-1, and 10 mils sodium hydroxide and 
shaken frequently for three hours; at the end of that time sufficient 
water is added to agglomerate the drug and after settling the solvent is 
decanted, clarified with magnesia and a few drops of water, and 100 mils 
filtered into a separator. It is then shaken out three times with water, 
acidulated with acetic acid, the acid solution rendered alkaline and ex- 
tracted with ether chloroform 1-1, the solvent evaporated and the residue 
dried at 100° C. and weighed. 

ASSAYS OF EXTRACTS 

Most of the methods have referred to the whole drug, but they may 
be made readily applicable to the fluid or solid extract. Five to 20 mils 
of a fluid extract should be evaporated on clean sawdust and the mixture 
shaken out with the proper solvent. In the case of a solid extract 1-10 
grams are taken for a sample, dissolved in water and alcohol and treated 
by the proper procedure for the drug in question. 

The assays thus far have in all cases referred to a single drug and 
not to mixtures. When dealing with mixtures, which is usually the case 
in the examination of medicines, modifications will necessarily be in order 
and preliminary to this a qualitative analysis must be performed. Em- 
phasis on this point cannot be made too strong. When the qualitative 
examination has shown the component parts of the preparation in question 
a line of procedure can then be mapped out looking toward a quanti- 
tative separation, 

THE LLOYD PROCEDURE OF DRUG ASSAY 

Before closing the chapter on drug assays, special reference must be 
made to the absorption method of assay which recently was brought for- 
ward by Dr. John Uri Lloyd. A colloidal form of hydrated aluminum 
silicate is employed, to which the name Lloyd's reagent has been given. 
On adding it in proper amount to an acid solution of an alkaloid, the alka- 
loidal salt is brought down. 

1 Apoth. Zeit., 1906, 21, 41-45, 53-56. 



CRUDE DRUG ASSAYS 69 

By this method all aqueous solutions of alkaloidal salts, so far as Dr. 
Lloyd has yet determined, will immediately yield the alkaloid, in the form 
of a precipitate, for the contact with this colloidal reagent destroys the 
tendency to remain in suspension, the precipitated compound quickly 
falling to the bottom of the vessel. It is insoluble in water. 

From this precipitate, the free alkaloid can be immediately separated 
by the addition of an alkali, and by extraction with an appropriate solvent, 
for in the presence of an alkali, the alkaloidal attraction of the reagent 
is instantly destroyed. 

This destroying of the qualities of the reagent, is, however, but a 
" paralysis " in the presence of the alkali, for after the alkaloid is sepa- 
rated from it, the washing of the residue with a dilute acid brings back 
to it all its original qualities. 

Each alkaloidal salt has an individuality in its affinity for the reagent, 
the amount necessary for the precipitation ranging from 6 grams of the 
reagent with 1 gram Codein Sulphate, to 10 grams of the reagent with 
Quinin Bisulphate in neutral solution, while in acidulated solution, 1 
gram of Quinin Bisulphate requires 12 grams of the reagent. 



The following table will be of interest: 






1 gram Cocain Hydrochlorate 


requires 


14 grams of the reagent 


1 " Strychnin Sulphate 


u 


10 ' 


i a 


1 " Morphin Sulphate 


a 


" 6 ' 


i a 


1 " Brucin Sulphate 


u 


8 ' 


i (( 


1 " Codein Sulphate 


a 


6 ' 


i ti 


1 " Cinchonin Sulphate 


CI 


10 ' 


i a 


1 " Cinehonidin Sulphate 


ic 


11 ' 


( u 


1 " Atropin Sulphate 


(t 


8 ' 


( a 


1 " Quinin Bisulphate (neutral) 


a 


10 ' 


( a 


1 " " " (acid) 


a 


12 ' 


1 " 



The assay of crude drugs by Lloyd's procedure follows the directions 
given under Hydrastis, page 46. 

Dr. Lloyd states that practically all crude alkaloidal drugs can be 
assayed providing the proper solvents be employed. 



Part II 

ALKALOIDAL DRUGS, ALKALOIDS AND 
MEDICINALLY ALLIED SUBSTANCES 



CHAPTER III 

DEFINITION AND GENERAL METHODS OF SEPARATION 
AND IDENTIFICATION 

The term alkaloid is, in general, limited to those organic bases which 
are found in the organism of the plant. But as it is necessary to include 
under the classification of alkaloids those artificial basic substances which 
of late have become very important in medicine, and which both in com- 
position and reactions are closely related to the natural bases, the limita- 
tion of origin requires an exception. 

The alkaloids do not form a well-defined group in a rational classifi- 
cation of organic compounds. They are usually complex substances. They 
all contain nitrogen, but rarely more than two atoms to the molecule, 
exceptions being in the Xanthin group and some of the rarer bodies, 
though there may be from twenty to forty carbon atoms. The basic 
property of the greater number is shown by the ease with which they 
form well-defined salts with acids, and the fact that they are not removed 
from acid solutions by immiscible solvents; but this is not invariable, 
and with some bodies the salts are unstable, being decomposed by water 
alone, and the alkaloid will have distinctly acid properties and will be 
removed from an acid aqueous solution by immiscible solvents. 

The greater number have been found to be derivatives of pyridin and 
quinolin, while there are many that cannot be correlated with these bases. 
Caffein and theobromin possess a constitution which is in no way related 
to pyridin, being derivatives of uric acid. 

Betain and muscarin, together with cholin and also sinapin, form a 
special group of quaternary bases, closely related to the amines of the 
aliphatic series. The weak bases, leucin and glutamin, which are decom- 

71 



72 ALKALOIDAL DRUGS 

position products of albuminoid matter, and which have been found in 
numerous plants, belong to the amido acids of the aliphatic series, the 
asparagines. 

They are nearly all solids, though coniin, nicotin, spartein, pelleti- 
erin, trimethylamin, and some other lesser known alkaloids, are liquids, 
and others, as physostigmin, scopolamin, usually appear in the liquid 
state, being very hygroscopic. Most of them are sparingly soluble in 
water, but usually soluble in alcohol and chloroform, benzol and ether, 
and their solutions are generally alkalin and bitter. The salts are formed 
by the direct union of a base with an acid, without the separation of water, 
and as a rule the salts are soluble in water. 

The hydrochlorides resemble those of all amines, as well as the chlo- 
rides of the alkali metals and the ammonium bases, in forming crystal- 
line double salts with platinic chloride, mercuric chlorid, and auric chlo- 
ride. Most of the alkaloids may be precipitated from their acid solutions 
by potassio-mercuric iodide, potassio-bismuthic iodide, picric acid, tannic 
acid, phosphotungstic acid, and phosphomolybdic acid, and also by a 
solution of iodine and potassium iodide, the latter reagent precipitating 
a large number of alkaloids quantitatively. 

Separation and Purification of Alkaloids. — The chemist analyzing drugs 
and medicinal preparations will be called upon to identify and determine 
alkaloids in complex formulas at the same time that the other compo- 
nents are sought, and to separate, identify, and determine alkaloids where 
the object of the analysis is the determination of the alkaloids alone. The 
scheme of analysis to be pursued in the first instance has been fully elabo- 
rated in my work " Qualitative Analysis of Medicinal Preparations," 
Where the alkaloids alone are the substances sought the following pro- 
cedure will be found advantageous, the preliminary work depending on 
the character of the sample. If the material is of an animal nature, i. e., 
a stomach, intestine, liver, meat, or the like, it should be thoroughly dis- 
integrated in a meat chopper or sausage machine, the cleanliness of which 
has been previously ascertained, then mashed in a mortar to a pulp and 
incorporated with a little tartaric acid. The mixture is then transferred 
to a large beaker or Erlenmeyer flask, water added, the flask warmed on 
a water-bath and the digestion continued for several hours, stirring from 
time to time. The liquid is decanted and the mass washed two or three 
times with warm water, not in too large amounts, as it is desirable to pre- 
vent the final volume from becoming too unwieldy; a little alcohol is 
then added to the decanted liquid and washings, and if a cloudiness appears, 
more is added until a precipitate separates in flocks, the latter condition 
often being facilitated by warming. After the precipitate has settled, 
the liquid is decanted through a creased filter and the container and filter 
washed with dilute alcohol. The filtrate is then transferred to a large 



GENERAL METHODS OF SEPARATION AND IDENTIFICATION 73 

separator, ammonia added in slight excess, and the liquid shaken out 
four times with ether. A small amount of the ether from the fourth shake 
out is evaporated, the residue dissolved in a few mils of dilute sulphuric 
acid, filtered and tested with Mayer's reagent, and if a precipitate occurs, 
the shaking out with successive quantities of ether continued. The com- 
bined ethereal liquids are then run through a creased filter and evapo- 
rated, hastening the evaporation with an air current. 

If morphin is suspected, the shaking out with ether is dispensed with 
and the aqueous alcoholic solution, after filtering, is evaporated until 
nearly dry and the mass extracted several times with alcohol, filtering 
the solvent into an evaporating dish. After evaporating the alcohol, the 
residue is dissolved in dilute sulphuric acid, filtered into a separator, a 
slight excess of ammonia added and shaken out four or five times with 
chloroform-alcohol 2-1, the solvent being run off through cotton and evap- 
orated. 

The treatment of the crude alkaloidal residue obtained by either of 
these two methods will be considered later. 

If the original sample is a pill, tablet, evaporated extract or other solid 
substance partly insoluble in water, it should be extracted several times 
with warm 95 per cent alcohol (pills, tablets and other hard solids must 
be ground in a mortar) the solvent filtered and evaporated nearly to dry- 
ness. The residue is treated with dilute sulphuric acid and filtered into 
a separator, washing the dish and filter with warm water, the filtrate 
made alkaline with ammonia and shaken out until exhausted with Prolius 
mixture (ether 4, chloroform 1, alcohol 1) and if morphin is suspected, 
several final extractions with chloroform-alcohol 2-1 must be made. The 
combined solvent solution is then run through absorbent cotton or a 
creased filter and evaporated to obtain the crude alkaloidal residue. 

If the sample is an alcoholic liquid, water is added until gums and 
resins and other substances are precipitated and the liquid filtered into 
a separator, or if no alcohol is present the liquid is poured directly into a 
separator. Ammonia is added in slight excess and the mixture shaken 
out as described in the preceding paragraph. In the cjtse of aqueous 
mixtures containing a large quantity of sugar, the final shaking with 
chloroform-alcohol may produce an emulsion, and under these conditions 
the solution should be first evaporated until most of the liquid is driven 
off and the residue extracted several times with hot alcohol. The latter 
is evaporated, the residue treated with dilute sulphuric acid, filtered into 
a separator and shaken out with the solvent. 

The crude alkaloidal residue obtained by any one of the above pro- 
cedures is then treated with 10-15 mils of dilute sulphuric acid, warmed 
and the solution filtered into a small separator. The residue is treated 
twice more with small quantities of normal sulphuric acid which is run 



74 ALKALOIDAL DRUGS 

through the filter into the separator. After the liquid is cooled, it is 
shaken out four times with 25-mil portions of chloroform, the combined 
chloroformic extracts washed with 10 mils water, preserving the wash 
water and adding it to the acid liquid, the chloroform run through absorb- 
ent cotton lightly plugged in the stem of the separator and evaporated. 
The residue left on evaporating the chloroform will contain caffein, theo- 
bromin, colchicin, narcotin, hydrastin, geissospermin, piperin, quebrachin, 
antipyrin, anesthesin, subcutin, or propaesin. After evaporating the 
chloroform the acid solution in the separator is made slightly ammoniacal 
and shaken out three times with anhydrous ether, the combined ethereal 
liquids are washed once with 10 mils water, filtered into a beaker and 
evaporated. The ammoniacal liquid should then be shaken out with 
chloroform, the solvent washed, filtered and evaporated, and the ammonia- 
cal liquid finally extracted with chloroform-alcohol 2-1, the solvent filtered 
and evaporated. 

If a separation such as above described is made on an unknown mixture, 
the alkaloidal residue should be obtained in a tared beaker and weighed 
as it will often be necessary, especially in forensic work, to know the 
quantitative proportions. The final evaporation and in fact the dis- 
sipation of the last portions of the solvents in all evaporations during the 
procedure should be done with great caution as many of the alkaloids 
are volatile, below 100° C. In cases where delicate questions are involved 
the residue should be dried in vacuo over sulphuric acid or calcium 
chloride. 

In order to identify the constituents of the residue the procedure should 
be systematic and thorough, but if the quantity is especially small, a milli- 
gram or less, the tests employed must be carefully chosen and a procedure 
to be used in such a case will be discussed later. 

First let us consider the residue left on evaporating the chloroform 
used for shaking out the acid solution. A macroscopic examination will 
usually indicate the presence of caffein or theobromin. The residue is 
then dissolved in about 5 mils of chloroform and a couple of drops of the 
solution evaporated on watch glass, and the residue dissolved in 1 mil of 
dilute sulphuric acid, the acid solution is then treated with a drop of 
Mayer's reagent and any precipitate noted, which would occur if colchicin, 
narcotin, hydrastin, quebrachin or antipyrin are present, and of course, 
if none is obtained further tests for these substances are unnecessary. 
Then a few drops of the chloroform solution should be evaporated in a 
small dish, the residue removed on the end of the finger (previously well 
washed) and rubbed over the end of tongue when the physiological effect 
of piperin and the synthetic anesthetics will be noted. A murexide test is 
then to be performed for the purpose of detecting caffein and theobromin 
on another portion of the evaporated chloroform solution. Then other por- 



GENERAL METHODS OF SEPARATION AND IDENTIFICATION 75 

tions are evaporated and tested respectively with nitric acid, Froehde's 
reagent, formaldehyde sulphuric acid and any characteristic coloration 
due to colchicin, narcotin, hydrastin, geissospermin or antipyrin noted. 
Further tests for substantiating the particular alkaloid indicated will be 
found under the detailed description of the individual. 

The examination of the alkaloidal residue from the alkaline solution 
when the amount is comparatively large should be as follows: After 
noting the odor which will be characteristic if nicotin, coniin, spartein are 
present, the whole amount is dissolved in 10-15 mils of chloroform and 
a drop of this solution on evaporation tested with Mayer's reagent to 
determine whether an alkaloid is actually present, and then a small por- 
tion is tested physiologically on the tongue for the presence of coca alka- 
loids, anesthetics, and aconitin. Next a residue in a small evaporating 
dish is treated with two drops of concentrated sulphuric acid and the color 
noted; red indicating sanguinarin and lobelin; yellow to red, sabadin, 
sabadinin, and atisin; blue, geissospermin or quebrachin; then on dilu- 
tion with a few drops of water and pouring into a small test-tube, a fluor- 
esence will be noted if quinin and some of the cinchona alkaloids are present. 
The same quantity of residue is then treated with sulphuric acid contain- 
ing potassium bichromate in solution and freshly made, and any color 
change carefully noted; strychnin, yohimbin, gelseminin, papaverin, and 
quebrachin will be indicated by this test. Another residue is then treated 
with a few drops of concentrated nitric acid and the color carefully noted ; 
brucin, aconin, morphin give a red color, sanguinarin orange, physostigmin, 
yellow soon turning orange; ipecac alkaloids orange; codein, yellow with 
the crystals orange until dissolved; heroin, yellow gradually becoming 
green; veratrin, pink rapidly fading; orthoform, blue changing to red; 
gelsemin, gelseminin, and geissospermin purple red; after noting the color 
in the cold the acid is evaporated on the steam-bath, antipyrin will be 
indicated by the appearance of a purple color and physostigmin gives a 
blood-red residue turning deep green and gelsemin a blue green. After 
the last traces of acid are evaporated the dish is cooled and a few drops 
of alcoholic potash added and the color and odor noted; strychnin, 
yohimbin, atropin, hyoscyamin, scopolamin and antipyrin give a purple 
color; holocain, nirvanin, novocain, orthoform and subcutin, red; the odor 
test is especially characteristic; cocain, aconitin, tropacocain, and stovain 
giving ethyl benzoate, which in the latter case is accompanied by isoni- 
trile, and on warming this may be accentuated ; a disagreeable odor appears 
in the presence of alypin, holocain, and nirvanin; euphthalmin gives off 
the odor of benzaldehyde and ethyl cinnamate is noticed if the cinnamyl 
bases of coca leaves are present. 

Another portion of the residue is now treated with a few drops of sul- 
phuric acid containing formaldehyde, which will give purple colorations 



76 ALKALOIDAL DRUGS 

of varying degrees of intensity and shades when certain of the opium 
alkaloids and their allied synthetic derivations are present; these include 
morphin, codein, heroin, dionin, apomorphin, narcotin, papaverin, apo- 
codein. Aconin gives a blue color and subcutin salmon, but the latter 
would have come out in the acid shake out. 

These tests will indicate a large number of the alkaloids commonly 
met with except pilocarpin and pelletierin. Microchemical tests should 
now be resorted to. A portion of the chloroform solution is evaporated 
and the residue dissolved in a few drops of very dilute hydrochloric acid, 
drops transferred to separate microscopic slides and tested respectively 
with reagents which give characteristic microscopic precipitates. 

It will often be found useful to test the physiological action of an alka- 
loidal residue on a cat's eye, and to prepare the solution for making this 
test, the amount reserved should be dissolved in a small quantity of dilute 
acetic acid, filtered, and brought to neutrality with sodium bicarbonate. 
The solution may be applied with a medicine dropper and to one eye only 
of an individual subject, the animal being strapped to a trough-shaped 
apparatus specially designed for this sort of work. After the operation 
the animal ought to be liberated and returned to the cage and observa- 
tions of the effect of the drug made from time to time. Atropin, homat- 
ropin, hyoscyamin, scopolamin, gelseminin, and gelsemin produce dila- 
tion; physostigmin and pilocarpin cause contraction, though in case of 
the latter dilation will occasionally take place. 

Returning now to a discussion of the procedure to be observed in the 
case of very small residues, one must first take into consideration the 
question involved. If it is a toxicological case the tests must be chosen 
with care after first obtaining all the information possible regarding the 
history of the case. No hard-and-fast rule can be laid down until one 
has familiarized himself with these facts. The residue should be dissolved 
in 5 mils of chloroform and several drops evaporated on microscopic slides, 
the residues dissolved in weak acid and precipitated with reagents giving 
the most characteristic precipitates and their forms observed under the 
microscope. Cocain, strychnin, codein, heroin, morphin, atropin, hyos- 
cyamin, scopolamin, aconitin, and some of the synthetic anesthetics 
should be especially sought for in this examination. Then test small 
fractions of the solution after evaporation as described above with sul- 
phuric acid and bichromate, nitric acid and alcoholic potash, formalde- 
hyde-sulphuric acid, and by the physiological tongue test. 

Microchemical Examination of Alkaloids. — The identification of alka- 
loids by a microscopic examination of the precipitate obtained on adding 
a reagent to a dilute solution of the specimen has assumed considerable 
importance during the last few years and has been a marked step in the 
progress of analytical chemistry. Howard and Stephenson took up the 



GENERAL METHODS OF SEPARATION AND IDENTIFICATION 77 

work in 1908 at the Bureau of Chemistry, beginning a systematic investi- 
gation of the action of all possible reagents on all the pure alkaloids obtain- 
able in order to determine and sift out the characteristic forms, to deter- 
mine the effect of an alkaloid on another and finally to work out a scheme 
of analysis based on the results obtained. They have made consider- 
able progress in the direction contemplated, but their results have never 
been published in full. 

In making these tests it is desirable to have the alkaloids in a solution 
diluted from 1-100 to 1-200. The reagents giving the greatest satis- 
faction include N/10 iodine, 10 per cent platinic chloride, 5 per cent pal- 
ladous chloride, gold chloride, picric acid, potassium permanganate, potas- 
sium chromate, chromic acid. A drop of the solution to be tested is 
transferred to a microscopic slide, the instrument adjusted and then a 
drop of the reagent added and the observation made. It will be neces- 
sary in some cases to start the crystallization by stirring the liquid with 
a glass rod. Another procedure consists in transferring a bit of the alka- 
loidal residue to a slide by means of a needle or glass rod, dissolving it in 
a drop of dilute hydrochloric acid and then adding the reagent. 

Strychnin is one of the easiest substances to detect microscopically. 
Howard notes thirty-six crystalline precipitates given by this alkaloid. 
Berberin, tropacocain, and cocain also react well with reagents, and 
Howard's notes on the reactions given by the latter are detailed under 
the analytical properties of cocain later in the book. 

Putt, 1 working with iodine, platinic chloride, and palladous chloride 
as reagents, has reproduced a number of plates showing the crystalline 
precipitates given by morphin, codein, dionin, atropin, /3-eucain, cocain, 
nicotin, antipyrin, strychnin, and heroin. 

Grutternik 2 experimented with the ammonium salts of various organic 
acids as precipitants and reports as especially suitable the following: 
ra-nitrobenzoic acid for strychnin; p-nitrobenzoic acid for strychnin 
and tropacocain; dinitrobenzoic acid for hydrastin, novocain, brucin, and 
strychnin; trinitrobenzoic acid for novocain, tropacocain, strychnin, bru- 
cin and coniin; dihydroxybenzoic . acid for cinchonin; trihydroxybenzoic 
acid for quinidin; mellitic acid for quinidin and cinchonidin; naphtha- 
lene sulphonic acid for cocain and strychnin; p-nitrophenylpropiolic acid 
for hydrastin, hydrastinin, strychnin, tropacocain, cinchonidin, and nicotin. 

Seiter and Enger 3 have recorded the results of their investigations 
on the precipitates given by cocain and some of the synthetic anesthetics 
with gold and platinum chlorides, chromic acid, and permanganate. The 
residue under examination is made up to 20 per cent solution with dilute 

1 Jour. Ind. and Eng. Chern., 1912, 4, 508-12. 

2 Z. anal. Chem., 1912, 51, 175-234. 

2 Am. J. Pharm., 83, 195-201; 265-8. 



78 ALKALOIDAL DRUGS 

hydrochloric acid for the permanganate test and diluted to 1 per cent 
for the others. Cocain is the only common anesthetic giving a precipi- 
tate with permanganate; alpha- and beta-eucain and holocain give pre- 
cipitates with platinic chloride differing from cocain; alpha-eucain and 
stovain give precipitates with gold chloride differing from cocain; with 
chromic acid cocain alone forms crystals. Seiter states further that in 
dilutions of 1-3000 cocain can be detected by treating 1 mil of the solution 
with 1 drop 25 per cent sulphuric acid and 1 mil saturated permanganate, 
allowing it to stand for some time and examining a drop of the mixture 
on a slide for the characteristic violet-red rectangular plates; alphaeucain 
at 1-600 gives crystals resembling ammonium-magnesium phosphate. 

The subject of the micro-analysis of alkaloids and certain other plant 
principles is featured by Kraemer in his " Botany and Pharmacognosy." 

Quantitative Estimation of Alkaloidal Residue. — It is a good rule 
always to make the evaporation of the final extraction of an alkaloid in 
a tared beaker and weigh the residue. The worker will then have made 
his quantitative estimation regardless of the character of the residue and 
he can then proceed to identify the mixture. If the alkaloid is extracted 
according to the method which has been detailed on the preceding pages 
and all the precautions taken to avoid loss by spurting and contami- 
nation with the salts dissolved in the aqueous liquids, and the final men- 
struum filtered through cotton, the weight of the residue will give the best 
determination of the quantitative value of the preparation under con- 
sideration. This statement is especially true when one is working with 
drugs containing more than one alkaloid, a condition which will obtain 
in the majority of instances with natural drugs. A residue obtained from 
coca leaves never consists entirely of pure cocain, from nux vomica of 
strychnin alone, and any titration or precipitation method must take for 
its factor either the molecular weight of cocain or strychnin, or the mean of 
mixtures, the exact proportions of the ingredients of w T hich are never the 
same. When working with a mixture containing but a single alkaloid, 
the latter, after a careful extraction, can be titrated with satisfactory 
results. The writer has often checked volumetrically the figures obtained 
in a gravimetric estimation of a single alkaloid extracted according to 
the previous directions and obtained figures which showed that the alka- 
loid was in a state of practical chemical purity. 

For making a volumetric estimation, the residue should be dissolved 
in 50 mils of N/50 sulphuric acid and titrated back with N/50 potassium 
hydroxide, using methyl red as an indicator. It w T ill be necessary often 
to warm the acid to hasten solution and one should be cautious that any 
ring of alkaloid which often collects near the rim of the beaker is dissolved 
by the acid. The residue may also be dissolved in a few mils of neutral 
alcohol and then treated with the acid. 



GENERAL METHODS OF SEPARATION AND IDENTIFICATION 79 

TABLE OF THE FACTORS FOR N/50 ACID 

One mil of N/50 Sulphuric Acid V. S. is the equivalent of: 

Gram 

Sulphuric acid 0.0009809 

Aconitin 0.012907 

Atropin 0.0057838 

Cinchona, combined alkaloids of 0.0061841 

Cinchonidin 0.005884 

Cinchonin 0.005884 

Cocain 0.0060636 

Coniin 0.002543 

Hydrastin 0.0076636 

Ipecac, combined alkaloids of . 0048034 

Morphin, anhydrous . 0057032 

Morphin, crystallized 0.0060636 

Physostigmin . 005504 

Pilocarpin 0.004163 

Quinin, anhydrous 0.0062842 

Strychnin 0.006684 

Heikel 1 has worked out a method of determining alkaloids in solution 
by adding an excess of Mayer's reagent and titrating the excess of mercury 
with potassium cyanide and silver nitrate. A solution of the alkaloid 
is made containing 0.1 gram in 10 mils; Mayer's reagent is then added 
to 10 mils of the solution until there is about 15 mils in excess; the liquid 
is diluted to 100 mils, shaken, filtered and 80 mils of the filtrate treated 
with 10 mils of dilute ammonia and 10 mils N/20 potassium cyanide which 
precipitates all of the mercury. The mixture is then neutralized or acidi- 
fied with dilute sulphuric acid and N/20 silver nitrate added until there 
is a permanent turbidity. From this titration the amount of mercuric 
chloride actually precipitated by the alkaloid can be determined. 

TABLE SHOWING THE WEIGHT OF ALKALOID CORRESPONDING TO 
1 MIL N/20 MAYER'S REAGENT 
Aconitin 0.0159 gram 

Atropin . 0093 gram 

Berberin . 0092 gram 

Brucin 0.0112 gram 

Quinin \ 

and I 0.00895 gram titration in neutral solution 

Quinidin J 
Quinin ^ 

and I 0.00514 gram 

Quinidin J 
Cinchonin \ 

and I . 0087 gram titration in neutral solution 

Cinchonidin J 
Cinchonin j 

and I 0.00514 gram 

Cinchonidin J 
1 Chem. Zeit., 1908, 32, 1149-50, 1162-63. 1186-87, 1212-13. 






80 ALKALOIDAL DRUGS 

Cocain 0.0082 gram 

Colchicin 0.00144 gram 

Heroin 0.00122 gram 

Hydrastin 0.00116 gram 

Hyoscyamin . 0093 gram 

Ipecac alkaloids 0.00895 gram 

Morphin 0.0104 gram titration in neutral solution 

Morphin 0.0811 gram 

Physostigmin 0.0084 gram 

Pilocarpin I 0.00765 gram amorphous precipitate 

Pilocarpin II 0.00369 gram crystalline precipitate 

Spartein 0.00213 gram 

Strychnin 0.00835 gram 

Veratrin 0.0192 gram 

Classification of Alkaloids. — The alkaloids and the drugs in which 
they occur will be discussed in the following order. The classification 
is based on that of Pictet, but it has been modified in so far that certain 
alkaloids of unknown or indefinite composition have been described under 
the same group as those having a known derivation, the change being 
advantageous on account of similarities in chemical properties and med- 
ical usage. The names in large type signify the bases whose composition 
has been definitely or with reasonable certainty established, or which 
have been classified according to derivation. 
Alkaloids derived from pyridin. 

CONIUM ALKALOIDS 

PIPERIN 

ARECA ALKALOIDS 

PILOCARPUS ALKALOIDS 

SPARTEIN 

Lobelin 

CYTISIN 

Delphinium alkaloids 

Piturin 
Alkaloids derived from pyrrolidin. 

SOLANUM ALKALOIDS 

POMEGRANATE ALKALOIDS 

COCA ALKALOIDS 
Alkaloids derived from quinolin. 

CINCHONA ALKALOIDS 

Yohimbe alkaloids 

Quebracho alkaloids 

Pseudocinchona alkaloids 

Angostura alkaloids 

Alstonia alkaloids 

Geissospermum alkaloids 






GENERAL METHODS OF SEPARATION AND IDENTIFICATION 81 

Alkaloids derived from isoquinolin. 

OPIUM ALKALOIDS 

Ipecac alkaloids 

HYDRASTIS ALKALOIDS 

Berberis alkaloids 

Calumba alkaloids 

CORYDALIS ALKALOIDS 

Celandine alkaloids 

Sanguinaria alkaloids 
Alkaloids which probably contain a pyridin nucleus but in a condition 
of condensation as yet unknown 

STRYCHNOS ALKALOIDS 

PEGANUM HARMALA ALKALOIDS 

ACONITE ALKALOIDS 

VERATRUM ALKALOIDS 
Alkaloids containing no pyridin nucleus. 

COLCHICIN 

XANTHIN BASES 

ERGOT ALKALOIDS 

MUSTARD SEED ALKALOIDS 
Alkaloids of unknown composition. 

Physostigma alkaloids 

Anhalonium alkaloids 

Pareira alkaloids 



CHAPTER IV 

ALKALOIDS DERIVED FROM PYRIDIN 

CONIUM ALKALOIDS 

Coniin, CgHnN 

Methyl-coniin, C9H19N 

Gamma-Conicein, CgHisN 

Conhydrin, C 8 Hi 7 NO 

Pseudo-conhydrin, CgHiyNO 
The hemlock, Conium macula turn L (Umbelliferse), contains these 
bases in combination with vegetable acids. They are found in all parts 
of the plant, but particularly in the fruit before it is fully ripe, the fruit 
being the portion used as the drug. It is seldom adulterated, being used 
itself more as an adulterant of anise, which it closely resembles in appear- 
ance. The alkaloids are all volatile and occur in the fruit to the amount 
of 0.5 to 1.5 per cent, the average being about 1 per cent. Coniin pre- 
dominates, in fact the proportions of the other alkaloids are very small, 
conhydrin, the next in quantity, being present in only about one-twentieth 
the quantity according to Wertheim. Taylor in the new edition of Allen 
also records the presence of ethyl-piperidin, but does not give any detailed 
description of its occurrence or properties, and it is not mentioned by 
Pictet or Bruhl. It has been claimed that coniin is present in Sambucus 
nigra. 

Conium extract and the alkaloid coniin have but a limited use in medi- 
cine. The extract is used in preparations which are used for controlling 
spasmodic affections like whooping cough, also in chorea and in certain 
forms of insanity. It is employed in palliatives for cancerous and scrof- 
ulous ulcers and tumors, and in certain forms of skin diseases. In plasters 
it is sometimes combined with belladonna for intercostal neuralgia. In 
ointments it is used for fissures and hemorrhoids. In fluid extract 
dandelion compound it occurs combined with Taraxacum and Podo- 
phyllum. 

In the form of pills or tablets, Conium extract is combined with aloes, 
ferrous sulphate, and ginger; with ipecac; with cubeb and glycyrrhiza; 
with mercurous iodid, lactucarium and opium in syphilitic compounds; 

82 



ALKALOIDS DERIVED FROM PYRIDIN 83 

and with Hyoscyamus, ignatia, opium, belladonna leaves, stramonium, 
aconite leaves and Cannabis sativa in a neuralgic idiopathic formula. 
In the liquid form we find elixirs of Conium with pyrophosphate of iron. 
The pure alkaloid in the form of the hydrobromate is used in tablet tri- 
turates and hypodermatic tablets. 

Coiin. d-alphapropylpiperidia 



H 2 

C 



H 2 C 
H 2 C 



CH 2 

■v JCH — CH 2 — CH 2 — CH3 

N 
H 



Naturally occurring coniin is dextrorotatory and when pure is a color- 
less, oily liquid with a tobacco-like odor, which on dilution with water 
becomes mousey, and is the characteristic odor by which the alkaloid 
is recognized. Coniin darkens by age or by exposure to light. It melts 
at —2.50° C, boils at about 166° C, distills readily with steam or with 
alcohol vapor, and is volatile at the ordinary temperature. It has 
(a) D =+16.4° at 19°, but on dilution with solvents the rotatory power 
is diminished; the specific gravity is 0.8444 at 20° C. Coniin is soluble 
in water 1-50, the solution having a strongly alkaline reaction, and 
giving a pink color with phenolphthalein ; this coloration is not removed 
by chloroform, as is the case with nicotin under similar conditions. Coniin 
is readily soluble in alcohol, ether, petroleum ether, and other organic 
solvents. With carbon disulphide it forms a definite compound which 
remains in the form of needle-like crystals on evaporating the solvent. 

The hydrochloride of coniin is formed with great readiness. On invert- 
ing a beaker moistened with hydrochloric acid over a drop of the alkaloid, 
white fumes will be produced and the crystalline hydrochloride formed. 
The phenomenon is similar to that given by nicotin, but in the case of 
the latter an amorphous hydrochloride results. The hydrochloride may 
also be produced by passing dry hydrogen chloride through a solution of 
coniin in anhydrous ether. 

The pure alkaloid on exposure to bromine vapor is converted to a mass 
of white crystals. It is readily oxidized by bromine water, chromic, and 
nitric acid, butyric acid being given off, and easily recognized by its odor. 

It is precipitated by nearly all of the general alkaloidal reagents, but 
the solutions must not be too dilute. No precipitates are given by gold 
or platinic chlorides at dilutions of 1-100, while with nicotin precipitates 
will be obtained with these reagents with dilutions from 1-5000 to 1-10000. 



84 ALKALOIDAL DRUGS 

Coniin gives no precipitate with silicotungstic acid at a dilution greater 
than 1-5000, while nicotin in dilution of 1 part to a million will yield a 
precipitate. 

Gabretti 1 describes a test with sodium nitroprusside which consists 
in adding a solution of the reagent to a dilute solution of the alkaloid. 
No color is produced at first, but on stirring a red tint appears, finally 
turning yellow. The color is destroyed by acids and changed to bright 
yellow with alkalies. Nicotin does not give this reaction. 

This reaction is apparently due to the secondary amine-like character 
of the coniin molecule. Coniin when subjected to Simon's 2 test for sec- 
ondary amines, gives an orange-red color. The reaction is obtained by 
adding one drop to 3 mils of water followed by 1 mil of dilute acetalde- 
hyde in 50 per cent alcohol and 1 drop of 1 per cent sodium nitro- 
prusside. 

The reaction of coniin with carbon bisulphide has been elaborated 
by Dilling and applied as a test for coniin and the other alkaloids of hem- 
lock. About 0.5 mil of a strong alcoholic solution of the alkaloid is boiled 
with a few drops of bisulphide and then an excess of water added. The 
solution thus obtained is now divided and the portions treated with a 
few drops of solutions of copper sulphate, ferric chloride, ferric sulphate, 
nickel chloride, cobalt chloride, and uranium nitrate, which will produce 
different colors, and on shaking with ether or toluene the shades will usually 
go into the solvent. Coniin gives a red color with uranium nitrate and 
toluene which is especially characteristic. Nicotin does not give these 
reactions, but piperidin reacts in a way almost identical with coniin. 
The color obtained in the copper sulphate reaction is brown; with ferric 
chloride, brown; with ferric sulphate, purplish brown; with nickel or 
cobalt chlorides, green. Spartein and lobelin, two volatile alkaloids, give 
a greenish yellow or no color with copper. 

The crystalline salts of coniin include the hydrochloride melting 218°; 
hydroiodid melting 165°; hydrobromide melting 211°; picrate, small yel- 
low prisms melting 75°; aurochloride, golden yellow crystals melting 77°; 
and cadmio-iodide melting 118°; platinic chloride containing 1 molecule 
H2O melting 78°; anhydride 175°; picrolonate melting 195.5°. 

Coniin may be prepared synthetically by the reduction of allyl-pyridin 
in alcohol by sodium. The synthetic product is inactive, but when there 
is added to a very concentrated and rapidly evaporating solution of its 
bitartrate, a crystal of d-coniin bitartrate prepared from the natural 
coniin, the d-coniin salt will entirely crystallize out and the Z-coniin remain 
in solution; Z-coniin platinic chloride melts at 160°, Z-coniin aurochloride 
melts at 59°. 

1 Boll. Chem. Farm., through Pharm. J., 1907, 78, 59. 

2 Compt. rend., 125, 1897, 536. 






ALKALOIDS DERIVED FROM PYRIDIN 85 

Methyl-coniin 

H 2 
C 



H 2 C 
H 2 C 



CH 2 

CH • CH 2 • CH 2 • CH3 



N 

I 
CH3 

This alkaloid is a colorless, laevorotatory liquid, boiling 173-174°, with 
specific gravity .8318 at 24° C. 

7-Conicein. a-Propyltetrahydropyridin. 
H 2 
C 



H 2 CY ^CH 

H 2 C I Jc • CH 2 • CHo . CH 3 

N 
H 

Commercial coniin contains traces of this alkaloid. It is a colorless 
liquid, with an odor like coniin, boiling 171-172°, specific gravity .8825 
at 22.5° C, remaining liquid at —50° C, and optically inactive. It is 
but slightly soluble in water, the solution having a strong alkaline reaction. 
The a form may be prepared from coniin by decomposing the bromo- 
derivative with alkali, and is easily reduced to inactive coniin by tin and 
hydrochloric acid or sodium and alcohol. It yields a characteristic double 
salt with stannic chloride, melting 215° C. The auro-chloride melts at 
69-70°; picrate 62°; hydrochloride 143°; hydrobromide 139°; and hydro- 
iodide at 102°. 

a and coniceins are obtained by the action of phosphoric anhydride 
or fuming hydrochloric acid on conhydrin, the former is a liquid boiling 
at 158° and the later a volatile solid melting at 41°, boiling at 168°. 

Conhydrin 

Hv /OH 



C 



H 2 Ci |CH 2 

H 2 cl JcHCH 2 .CH 2 .CH 3 



N 
H 



86 ALKALOIDAL DRUGS 

Conhydrin crystallizes from ether in dextrorotatory colorless leaflets, 
melting at 118-121°, boiling at 220-225°, readily soluble in alcohol, 
chloroform and moderately soluble in water and ether. It sublimes easily, 
its odor resembles coniin, and it may be separated from commercial coniin 
by cooling the liquid to 5° C. collecting the separated crystals on glass 
wool, and washing with petroleum ether. Its aurochloride melts at 133- 
134°. Its proportion to coniin in hemlock is about 1-20. 

On heating conhydrin with phosphorus pentoxide in a sealed tube in 
an atmosphere of Irydrogen, /3-conicein results. 

Pseudoconhydrin 

This alkaloid is the stereo-isomer of conhydrin and crystallizes in vari- 
ous forms, melting at 100-106°, boiling at 230-236°, dextrorotatory 
(a) D = +10.98°, soluble in water and organic solvents. Its aurochloride 
on decomposition gives the normal conhydrin. On crystallizing out of 
petroleum ether the melting-point is 52-69°, but on warming, this form 
is converted to that having the higher melting-point, 133-40°. The 
platinochloride melts at 185-186°. 

J. von Braun 1 has evolved a procedure for the separation of the conium 
bases. The greater part of the coniin is first separated by fractional dis- 
tillation leaving the conhydrin in the mother liquor. The distillate is 
then treated with benzoyl chloride and sodium hydroxide, which gives 
benzoyl coniin and benzoyl-4-aminobutylpropylketone; the mixture is 
shaken up with ether, which removes the derivatives and the methyl coniin, 
and the latter is recovered by shaking out with dilute acid. The ether 
solution is then dried, concentrated, and treated with light petroleum 
ether, which precipitates the bulk of the benzoylaminobutylpropylketone. 
The solution is filtered, evaporated and distilled in vacuo up to 220° C, 
and the residue dissolved in ether and precipitated with petroleum ether, 
the precipitate being added to the rest of the ketone derivative from which 
the conicein is recovered. The distillate contains the benzoylconiin from 
which the alkaloid may be recovered. 

Quantitative Examination of Coniin Products. — The methods for the 
assay of the drug Conium have been described in the chapter on drug 
assaying. For fluid extracts or tinctures a quantity representing the 
amount of drug used in the assay should be evaporated on sand or washed 
sawdust and the procedure carried out as for the drug. 

When either the drug or a salt of coniin is present alone in a liquid 
product, the separation of the alkaloid can be effected very simply by 
diluting the mixture, rendering alkaline with sodium carbonate and shak- 
ing out three or four times with ether. The solvent is then shaken three 

1 Ber., 1905, 38, 3108. 






ALKALOIDS DERIVED FROM PYRIDIN 87 

times with dilute hydrochloric acid and the combined acid solutions washed 
once with ether (discarding the latter), made alkaline with sodium car- 
bonate, and the liberated alkaloid shaken out with three portions of ether. 
The ether solution is then washed with a little water, filtered into a tared 
beaker and evaporated with hydrochloric acid, using the precautions given 
under the assay of the drug. 

With tablet triturates and hypodermatic tablets, the simplest pro- 
cedure consists in putting 10-25 tablets into a large separator, adding 
water, shaking until the tablets are disintegrated and then adding excess 
of sodium carbonate. The alkaloid may be then removed by ether and 
the determination continued as described under liquids above. 

In the case of pills or tablets where there is considerable mass and 
usually a heavy sugar coating, the sample must be ground up in a mortar 
and triturated three or four times with 95 per cent alcohol, filtering the 
alcoholic extract into an evaporating dish and evaporating the bulk of 
the solvent. The contents of the dish are then treated with dilute sul- 
phuric acid and the liquid filtered into a separator, thoroughly washing 
the dish and filter with dilute acid. From this point the assay follows 
the directions given under liquids above. 

Determination of Coniin in a Mixture of Alkaloids. — As was noted 
above, coniin will sometimes be found present with the ipecac alkaloids, 
opium alkaloids, atropin, hyoscyamin, aconitin, and strychnin, and the 
simplest method of separation is by distillation with steam. In all cases 
it is advisable to first separate the combined alkaloids from the bulk 
of the product by ether, using any one of the above manipulations, depend- 
ing on the class of the material in hand, After obtaining an ether extract, 
which will contain all the coniin, it is shaken out with dilute hydrochloric 
acid and the acid transferred to a distillation flask connected up for steam 
distillation and fitted with a trap to prevent foreign substances from 
coming over mechanically. The acid solution is made alkaline with 
sodium carbonate and the distillate received in a flask containing dilute 
hydrochloric acid. The liquid in the receiver is finally transferred to a 
separator, made alkaline with sodium carbonate and the assay for coniin 
completed as usual. 



PIPERIN, C 17 H 19 N0 3 



H 2 

! | I- 
I I 



H 2 r N iH 2 



H 2 C< N 

O-A /— CH=CH— CH=CH— CO 



88 ALKALOIDAL DRUGS 

This alkaloid occurs in the fruits of Piper nigrum, P. longum and 
other species, the first named being the chief source of the commercial 
pepper products. The dried berries are equal in size to a small pea, 
externally blackish, reticulated and wrinkled, internally whitish, with an 
undeveloped embryo. They contain from 4 to 10 per cent of piperin, 
a soft greenish resin, a volatile oil and the usual vegetable matter con- 
tained in leguminous plants. 

For medicinal use the oleoresin is prepared by extracting the powdered 
berries with ether and allowing the evaporated extract to stand until a 
portion of the piperin has settled out, when the soft resinous mass is 
strained through muslin. Both the oleoresin and the ground pepper are 
employed as stomachics and stimulants in colic, cholera morbus, flatu- 
lence, intermittent fevers, etc., and should be looked for in pills and tablets 
labeled anti-chill, anti-malarial, carminative, ague and stomach tonic. 
The alkaloid piperin is seldom used -by itself. Oleoresin of pepper will 
be found in combination with Cinchona bases, arsenic, colocynth, ferrous 
sulphate, Gelsemium, gentian, ipecac, aloin, and cloves. It has been com- 
bined with Prussian blue in chill remedies and occasionally used with 
strychnin in bitter tonics. 

Piperin crystallizes in pale 3 r ellow prisms melting 128-130°, almost 
insoluble in cold water, slightly soluble in ether, and readily soluble in 
alcohol, chloroform, benzol, and petroleum ether. It is a weak base and 
its salts formed with mineral acids are immediately decomposed by water. 
It is easily removed from an acid solution by means of petroleum ether. 
Its solutions are pungent. 

The hydrochloride dissolved in alcohol gives precipitates with alcoholic 
mercuric chloride, platinic chloride, and aqueous iodine in potassium iodide. 
The dry alkaloid gives an orange to blood-red color with concentrated 
sulphuric acid, and an orange-red resin with nitric acid, becoming blood- 
red when alkali hydroxides are added. 

On boiling with alcoholic potash it is hydrolyzed to piperidin and 
piperic acid. 

Ci 7 Hi 9 N03+H 2 = C5H11N+C12H10O4. 

The former substance is a volatile liquid and a strong base, boiling 105°, 
soluble in water, alcohol, ether and benzol. Piperic acid, on oxidation 
with permanganate, is converted into piperonal, which has the odor of 
heliotrope, and the formation of this substance by previous hydrolysis 
of the alkaloid is a test for the presence of piperin. 

PIPERIDIN 

Piperidin has an unpleasant ammoniacal odor. It boils at 106° C. 
and is soluble in all proportions in alcohol and water. Its aqueous solu- 



ALKALOIDS DERIVED FROM PYRIDIN 89 

tion precipitates metals similarly to ammonia, but the zinc and copper 
compounds are not soluble in excess. The aurochloride crystallizes from 
alcohol in leaflets, melting 218-229°, with decomposition, and when 
obtained from alcohol, the crystals contain one molecule of the solvent 
and melt at 191°. The picrolonate melts at 142° with decomposition. 

Piperidin gives a blue color when treated in aqueous solution (1 drop 
to 3 mils) with 1 mil of dilute acetaldehyde solution and 1 drop of 1 per 
cent sodium nitroprusside. The blue color changes through greenish blue 
to pale j^ellow. This is a general reaction for secondary amines. 

Piperidin reacts with a freshly prepared solution of gallic acid, produc- 
ing a pale-rose color turning deep yellow; with pyrogallol, a yellow color 
appears at once, changing to brownish black; with catechol a violet color 
changing to pink and finally to yellow; with quinol, a yellow to deep 
brown. 

Piperidin reacts with carbon bisulphide to form piperyl dithiocar- 
bonate which crystallizes out of alcohol in lustrous plates, and which, 
when heated rapidly in a capillary tube, soften at 168° and melt at 
172-175° C. 

In analytical work one is not concerned with the quantitative esti- 
mation of piperin. In the general scheme of alkaloidal separation, the 
base will appear in the fraction obtained by shaking out the acid solu- 
tion with petroleum ether. The pungency of the residue will immedi- 
ately suggest piperin, and it may be further identified by its color tests, 
melting-point, and odor test. 

If it is contaminated with resinous matter the mass should be dis- 
solved in dilute alkali and shaken out with petroleum ether to remove 
the piperin. The alkaloid must then be further purified by recrystalli- 
zation from petroleum ether or ether before a determination of its melt- 
ing-point and color tests are made. Unless the substance is nearly color- 
less the color reactions will be unsatisfactory. 

The pungent principle of capsicum will also appear at this point, but 
it is readily distinguished from piperin by its failure to give the same 
color and odor tests. 

ALKALOIDS OF THE BETEL-NUT PALM 

Arecaidin, C 7 HnX0 2 or C s HnN0 2 . 

Arecolin, C8H13XO2. 

Guvacin, C6H9XO2. 

Arecain, C7H11NO2. 
The four alkaloids occur in the betel-nut, the fruit of Areca catechu 
(Palma?). The plant is native in Sunda and is cultivated in the Philip- 
pines and India. The fruit is used extensively as a masticatory. It 



90 ALKALOIDAL DRUGS 

is a grayish-brown, hard, conical-shaped seed, with numerous spiral red- 
dish veins. 

A fluid extract of the drug is astringent and has vermifugal properties. 
It is used for the expulsion of tape-worm and in veterinary practice, and 
the alkaloids may be anticipated in liquid products advertised as vermi- 
fuges. It is administered in the liquid form as the properties desired are 
credited to arecolin, which is volatile. Arecolin hydrobromide is used as 
a cathartic and anthelmintic in veterinary practice and as a myotic in 
the human eye. Arecolin-eserin is a mixture of equal parts of arecolin 
hydrobromide and physostigmin sulphate, it exhibits the combined thera- 
peutic properties of the components and is employed as a myotic and 
subcutaneously as a cathartic in veterinary practice. 

Arecolin 
H 

Hs/^-COOCHa 
H 2 x Jh 2 



N 

I 
CH3 

Arecolin is the chief alkaloid of the nut and on which its therapeutic 
activity depends. It is closely related to the other bases of this group 
in composition, but differs markedly in chemical and physical properties. 
It is a methyl ester of a tetra-hydro derivative of trigonellin. 

Arecolin is an oily liquid, colorless and odorless, volatile with steam, 
strongly alkaline and boiling 209°. It is soluble in water, alcohol, ether, 
and chloroform. 

Mayer's reagent gives a yellow, oily precipitate which soon crystallizes, 
iodine gives a brown oily precipitate, and picric acid a resinous precipitate, 
both of which finally crystallize. With potassium-bismuth iodide (Drag- 
endorff's reagent) a fine crystalline pomegranate red precipitate is obtained. 
The aurochloride is a yellow oil. No precipitates result with platinic or 
mercuric chlorides or tannic acid, but a platinochloride is precipitated 
when mixed alcoholic solutions of arecolin hydrochloride and platinic 
chloride are treated with ether. The sulphate, nitrate, acetate, hydro- 
chloride and hydrobromide are well-defined salts, the latter being the 
one of commercial importance and official in the German Pharmacopoeia. 

On saponification with acids or bases the oxymethyl group is split 
up and arecaidin results. The converse takes place on treating arecaidin 
with methyl alcohol and hydrochloric acid, and if methyl alcohol is 
replaced by ethyl alcohol, homoarecolin is formed, which resembles arecolin 
very closely. 



ALKALOIDS DERIVED FROM PYRIDIN 91 



Arecaidin 


H 2 

H 2 /^ C=0 


h 2 1 Jh 2 

N 



CH3 

Arecaidin crystallizes in plates containing 1 molecule of water, and 
when dehydrated melts with decomposition at 223-224°. It is readily 
soluble in water, with difficulty in alcohol, and insoluble in ether, chloro- 
form, and benzol. It forms salts with both acids and alkaloids. Its 
aqueous solution has a slightly acid reaction. It has no physiological 

acitivity. 

Guvacin 

O 



Of ]H— CH 3 

h 2 I x/ Jh 2 

N 

I 
H 

Guvacin crystallizes from alcohol in shining crystals which melt with 
decomposition at 271-272°. It is readily soluble in water and somewhat 
soluble in dilute alcohol, but insoluble in absolute alcohol and the other 
organic solvents. 

Arecain 

Arecain is n-methyl guvacin. It crystallizes with 1 molecule of water, 
which it loses at 100° and melts with decomposition at 213-14°. It solu- 
bility resembles that of guvacin. 

With the exception of arecolin none of these alkaloids is of importance 
in drug analysis. Arecolin may be separated from them by its solubility 
in the organic solvents and is markedly distinct from them in being 
volatile with steam. 

PILOCARPUS (JABORANDI) ALKALOIDS 

Pilocarpin, CnHi 6 N 2 2 . 
Isopilocarpin, C11H16N2O2, a stereoisomer. 
Pilocarpidin, C10H14N2O2. 
Jaborin, C11H16N2O2. 
These alkaloids occur in the leaflets of different species of Pilocarpus 



92 ALKALOIDAL DRUGS 

chiefly in P. microphyllus, P. jaborandi, P. pennatifolius, P. racemosus, 
of the family Rutacese. 

The botany of Pilocarpus has been for some time in a chaotic state. 
The distinguishing features of the leaves are often difficult to determine. 
The leaflets of two dozen species are sold commercially, some of which 
are devoid of alkaloidal content. The name " Jaborandi/' which is 
applied to the drug in the trade, and unfortunately to some extent in 
science, has virtually no meaning. It is attached to all species of Pilo- 
carpus regardless of their medicinal value. Among the trade the drug 
is denoted as Pernambuco, Paraguay, Maranham, Ceari, Aracati, Rio 
Janeiro Jaborandi, and others, and these designations all relate, either 
to the country in which the drug is grown, the port from which it is shipped 
into commerce, or they are the common names applied by the people, 
and the terms are meaningless considered in relation to the species. 

The leaflets are emarginate and the surface presents a multitude of 
transparent dots discernible when the leaf is held between the eye and a 
strong light, these two features distinguishing the drug from others of 
similar general appearance and from adulterants. They do not, how- 
ever, distinguish a valuable species of Pilocarpus from a worthless variety. 

Preparations of pilocarpus and Pilocarpin are used to a limited extent 
as expectorants, aperients, diaphoretics, sialagogues, sudorifics, and galac- 
tagogues; in hair tonics, remedies for Blight's disease, and in eye 
remedies for contracting the pupil. As a general thing the drug or the 
alkaloids are dispensed by themselves, and, except in the case of hair 
tonics, one will rarely meet with mixtures. Tablets of pilocarpin nitrate 
and hydrochloride are the forms in which the alkaloid is used, and the 
drug is used as its fluid, solid or powdered extract. 

Pilocarpin 

C 2 H 5 ^— CH 2 — C N\-CH 3 



II >CH 

Ol /H 2 HC N^ 



This alkaloid is usually seen as an oily syrup, as it is very hygroscopic, 
but it may be obtained in the anhydrous condition, and, when quite pure, 
is crystalline. It is readily soluble in water, solutions of caustic alkalies, 
alcohol, chloroform, and benzol, and less so in ether. The solutions of 
the alkaloid and its salts are dextro-rotatory, (a) d = +100.5°. It is con- 
verted into isopilocarpin by heating the hydrochloride for half an hour 
at 204-205°, or by distilling the free base in vacuo. An acid solution gives 
precipitates with Mayer's reagent and iodine, but none with potassium 
ferrocyanide nor tannic acid. Picric acid gives a precipitate in concentrated 



_ 



ALKALOIDS DERIVED FROM PYRIDIN 93 

solution acidulated with hydrochloric acid. It may be shaken out from 
weak ammoniacal solution but not from a solution of caustic alkali. 
Bromine acts on it at high temperatures giving bromcarpinic acid, 
CioHi5N 2 4 Br, melting 209°. 

Pilocarpin gives few color reactions on which any reliance can be 
placed, and none with the commonly used reagents. Helen's reaction 
gives good results and may be applied to a solution of the hydrochloride. 
From .01 to .02 gram of the salt is dissolved in a little water, 1-2 mils of 
an acid solution of hydrogen peroxide is added, followed by 2 mils of ben- 
zol and a few drops of a 0.3 per cent solution of potassium bichromate. 
On shaking, the benzol layer will become purple to blue in the presence 
of pilocarpin. Pyridin and quinolin both give a violet coloration under 
the same conditions, but the color soon fades; apomorphin gives a violet 
changing to green on separating the benzol and addition of dilute stan- 
nous chloride; antipyrin gives a blue color, distinguishable from that of 
pilocarpin by shaking the benzol layer with water containing a trace of 
hydrochloric or sulphuric acid, and treating this acid layer as before with 
peroxide, bichromate, and benzol, when the color will be regenerated, 
which is not the case with pilocarpin. Apomorphin is usually indicated 
long before it is finally separated from a mixture by the green color im- 
parted to the solution, and the reddish- violet color imparted to the solvents, 
on shaking out from alkaline solutions. 

Pilocarpin or its hydrochloride reduces calomel when intimately mixed 
with it, the reaction being similar to that produced by cocain. 

Pilocarpin forms certain well-defined salts, the nitrate melting 178°, 
the hydrochloride melting 204-205°, the hydrobromide melting 185°, the 
picrate melting 158-160°, the aurochloride melting 100°. 

Pilocarpidin 

This body occurs in very deliquescent crystals, strongly alkaline, 
soluble in alcohol, chloroform, and water and slightly so in ether and 
benzol. It is optically active. It possesses acid properties and unites 
with alkalies to form salts which are readily decomposed by carbon dioxide. 

Isopilocarpin 

This alkaloid bears a close resemblance to pilocarpin and its stereo- 
isomer. It has {a) D = +42.8°. It forms the same well-defined salts as 
pilocarpin, the nitrate melting 159°, the hydrochloride melting 127°, 
and hydrobromide melting 147°. 

Quantitative Determination. — As pilocarpin will seldom be found 
mixed with any other alkaloid, its determination may be accomplished 
without difficulty. In the case of tablets of pilocarpin hydrochlorate or 
nitrate, about twenty-five should be transferred to a separator, disinte- 



94 .ALKALOIDAL DRUGS 

grated with a little water, then ammonia added and the alkaline mixture 
shaken out three times with chloroform. The combined chloroform 
extracts are then shaken out with three portions of normal hydrochloric 
acid, and the pure alkaloid finally removed from this latter solution with 
chloroform after adding excess of ammonia. 

Pilocarpin may be determined in hair tonics by first removing the 
alcohol by distillation or evaporation, adding ammonia, shaking out the 
alkaloid with chloroform, and purifying it as in the case of tablet deter- 
mination. In case the first manipulation with chloroform is difficult, 
owing to emulsification, Prolius mixture can be substituted to advantage, 
and in the event of such a solvent being used it must be removed by 
evaporation before proceeding with the purification. 

SPARTEIN C 15 H 26 N 2 

H 2 
•CH 2 • CH \~ C ~/CH 2 • CH 2 \ 

HC— CH 2 • CH 2 — N N— CH 2 • CH 2 — CH 

\CH 2 • CH 2 / \CH 2 • CH 2 / 

This alkaloid occurs in the broom plant, Cytisus scoparius (Fabaceae), 
the tops of which are used medicinally. It is also reported by Willstatter 
and Marx as occurring in Lupinum luteus and L. niger. The alkaloid 
is usually applied in the form of its sulphate, it is laxative and diuretic, 
is employed in dropsy due to the heart, and in anasarca of chronic kidney 
disease, and may be expected in cardiac pills and tablets. Spartein sul- 
phate is sold alone in the form of tablet triturates and hypodermatic 
tablets, and in heart tonic mixtures in conjunction with Cactus grandi- 
florus, digitalin, strychnin, nitroglycerin, and strophanthin or with Stro- 
phanthus, caffein, and codein. Spartein has been used as an ingredient 
of treatments for the drug habit combined with morphin sulphate, heroin, 
caffein, pilocarpin, and carbolic acid. 

Pure spartein is a colorless, oily liquid, heavier than water, with an 
odor resembling anilin, and a very bitter taste. It darkens and thickens 
on exposure to air. When pure it boils about 320° C. under normal pres- 
sure. It is lsevorotatory in absolute alcohol, readily soluble in alcohol, 
ether, chloroform, and petroleum ether, slightly soluble in water and 
insoluble in benzol. 

It gives no characteristic color reactions with mineral acids. It is 
precipitated from solutions of its salts by a number of alkaloid reagents, 
and some of the salts obtained are crystalline with definite melting-points, 
the platinochloride melts 244-257° with decomposition, the aurochloride 
melts 175-180° with decomposition, the picrate melts 178-180°. It 
gives precipitates with Mayer's and Wagner's reagents, cadmium iodide, 



ALKALOIDS DERIVED FROM PYRIDIN 95 

sodium phosphomolybdate, silico-tungstic acid, potassium iodide,, bromine 
water,, etc. 

Spartein is volatile with steam. A piece of moistened red litmus paper 
held over a vessel containing the free alkaloid is gradually turned blue. 

An ethereal solution of iodine added to a solution of spartein in ether 
causes the precipitation of a black periodide. This substance may be 
dissolved in boiling alcohol and on cooling separates out in the form of 
green needles. An orange-red coloration is produced when spartein is 
treated with a drop of ammonium sulphydrate. An ethereal solution of 
spartein to which about 20 mg. of dry sulphur has been added, yields an 
abundant bright red precipitate on passing hydrogen sulphide. Coniin, 
when treated in the same way, gives an orange turbidity. 

Spartein is readily oxidized by calcium hypochlorite, hydrogen per- 
oxide, silver oxide, etc., and yields a series of oxysparteins. 

The ordinary form in which spartein occurs in the market is the sul- 
phate, CioH26N2-H2S04+5H20, which is a slightly hygroscopic salt, 
readily soluble in water and alcohol. 

When spartein is added to ferric chloride and potassium thiocyanate 
which have been spotted out on a porcelain plate and dried, a violet to 
reddish shade is obtained. 

When spartein hydriodide is heated with methyliodide two isomeric 
iodomethylates are formed. The hydriodides of these are decomposed 
by heat into methyliodide and spartein hydriodide, the latter being the 
same substance in both cases. Iso-spartein hydriodide, when treated 
with sodium carbonate, gives the free base which is an oil boiling at 177- 
179° C. at IQto m., insoluble in water, but soluble in the ordinary organic 
solvents, rotation (a) D = 25.01, specific gravity 1.02793 at 17° nd= 1.53319 
at 17°. It resembles spartein in all its reactions. 

Valeur 1 reports the isolation of a volatile alkaloid from the mother 
liquors from the crystallization of commercial spartein sulphate. This 
base, to which the name genistein, Ci6H 2 sX2, is given, melts 60.5° and 
boils at 177-178° at 22 mm. It does not reduce permanganate. It forms 
a picrate melting 215° and a platinochloride containing water which is lost 
at 110°, the anhydrous substance decomposing at 225° without melting. 

In the systematic scheme of alkaloidal analysis, spartein will appear 
in the petroleum ether shake-out from ammoniacal solutions. If it is 
suspected by preliminary tests, it may be readily separated from other 
alkaloids with which it may occur by a steam distillation and its identity 
established beyond question by appropriate tests, the most character- 
istic of which have been described above. 

To determine spartein, when it occurs as the sulphate alone in tablets, 
the sample should be disintegrated with water in a separator, treated 
ij. Pharm. Chim., 1913, 8, 573. 



96 ALKALOIDAL DRUGS 

with excess of ammonia and shaken out three times with ether; the ether- 
eal solutions are combined and shaken out with dilute hydrochloric acid, 
and the acid solution treated with excess of ammonia and shaken with 
ether; the ether, which now contains pure spartein, should be filtered 
into a tared flask and subjected to dry hydrogen chlorid gas in slight 
excess, the ether carefully evaporated and the residue warmed and sub- 
jected to a gentle blast to remove the excess of acid and then dried in a 
vacuum desiccator. 

In the case of mixtures the alkaloids should first be separated in a 
crude way by shaking out an ammoniacal solution with ether and chloro- 
form, and then extracting this ether solution with dilute sulphuric acid; 
the acid solution is transferred to a distilling flask fitted up for steam 
distillation, the bases liberated with fixed alkali and the spartein distilled 
over into dilute acid, from which it may be separated as previously 
described. Strychnin may be determined in the solution remaining in the 
distilling flask by shaking out with chloroform. Codein, if present, would 
probably be partly decomposed. 

Spartein can also be determined as the silicotungstate. The alkaloid, 
separated from the rest of the mixture in which it occurs by suitable 
means similar to that above described, is finally brought into solution 
in very dilute hydrochloric acid and precipitated by a 10 per cent solu- 
tion of silicotungstic acid or its potassium salt. The precipitate may be 
filtered onto a Gooch and dried at 100°. It has the composition SiC>2, 
12W0 3 , 2H 2 ; 2C15H26N2+7H2O. 

LOBELIN 

Lobelin is an alkaloid of Lobelia inflata (Lobeliacese) , Indian tobacco, 
the leaves and tops of which furnish the drug which is used extensively 
in asthma remedies. There are other species of Lobelia which are used 
medicinally, L. cardinilis, cardinal flavor, and L. syphilitica. The con- 
stituents of these subsidiary drugs have not been determined, the first 
named has been used as an anthelmintic and the latter as an antisyphilitic. 

Extract of lobelia and lobelin sulphate are employed medicinally. The 
extract will be found with Sanguinaria and skunk cabbage, in fluid extract 
lobelia compound, and in tablets and elixirs recommended for asthma 
and croup where it is mixed with bromides and iodides, nitroglycerin 
and Euphorbia pilulifera. 

The crude alkaloid has an odor suggestive of honey and tobacco, but 
is odorless and colorless when pure. It is a volatile, amorphous base, 
permanent in the air, slightly soluble in water, but dissolving in all the 
ordinary organic solvents including petroleum ether. As ordinarily ex- 
tracted from mixtures or the drug it will be obtained as a yellow syrup. 



ALKALOIDS DERIVED FROM PYRIDIN 97 

It is precipitated by the usual alkaloidai reagents and gives a very 
insoluble compound with tannic acid. 

Sulphuric acid gives a red color and nitric acid yellow. When warmed 
with 10 per cent alkali containing 4 per cent permanganate, benzoic acid 
is formed, which may be separated by filtering, acidifying, and shaking 
out with ether. 

Lobelin sulphate is hygroscopic. 

In the usual scheme of medicinal analysis lobelin will appear in the 
fraction obtained on shaking out the alkaline solution with petroleum ether. 
When the solvent is evaporated the alkaloid will be left as a yellowish oily 
or syrupy liquid having the characteristic odor above mentioned. Residues 
of lobelin should not be heated after the solvent is evaporated on account 
of the volatility of the base. This property may be used to advantage 
in separating lobelin from sanguinarin in case it is desired to test for both 
in the same residue. They both give a red color with sulphuric acid, 
and while lobelin would probably be indicated by its odor, the presence 
of sanguinarin could only be ascertained with certainty by removing the 
lobelin by distillation. It may be observed, however, that while lobelin 
may be to a considerable extent removed from an alkaline solution by 
petroleum ether, very little sanguinarin will come out at this point. 

The analyst should look carefully for lobelin in asthma, catarrh, and 
hay fever cures, especially in those which are advertised extensively to 
the laity. It is probably employed to a larger extent than is credited 
owing to the fact that it would be easily lost or overlooked. 

CYTISIN 

Cytisin occurs in a number of minor drugs, among which may be 
mentioned Baptisia tinctoria (Fabacese), wild indigo, used principally 
as an antiseptic in washes and ointments; Cytisus laburnum, false ebony, 
which has been recommended in whooping cough, vomiting, bronchitis, 
and asthma; Euchresta horsfieldii, a Javanese pea used as a contra-poison 
by the natives; Genesta tinctoria, used as a cathartic and sometimes as 
a diuretic in dropsy; and in several species of Sophora and Ulex. It is 
identical with several alkaloids to which formerly different names were 
applied, ulexin, baptitoxin, and sophorin. 

B. tinctoria is probably the only drug which the analyst will encounter 
in ordinary practice. With the oils of eucalyptus and gaultheria, boric 
acid, menthol, and thymol it is used in the composition of antiseptic 
washes of the type resembling " listerine." 

Cytisin, C11H14N2O, is a diacid base readily soluble in water, alcohol, 
and chloroform, but only sparingly in ether or petroleum ether. It crys- 
tallizes from alcohol in prisms which melt 152-153° or at 156° when 



98 ALKALOIDAL DRUGS 

thoroughly dried; it is laevorotatory and strongly alkaline, easily displac- 
ing ammonia from its salts. According to Mullikin it may be removed 
from acid solution by means of chloroform. It may be sublimed 
unchanged in a vacuum. Its salts are crystalline and in some cases two 
types have been prepared. The aurochloride melts 212-213° and is veiy 
insoluble. Two platinochlorides are known and are much more soluble 
than the gold salt. The compound with mercuric chloride is character- 
istic. It gives precipitates with the usual alkaloidal reagents. 

Cytisin gives a red color with ferric chloride which is very character- 
istic and sensitive even with minute amounts. The red color is destroyed 
by hydrogen peroxide, and on warming the liquid a blue color is produced. 
Sulphuric acid added to cytisin gives no color reaction, but on adding 
thymol and warming a yellow color appears, soon becoming red. Bichro- 
mate added to a sulphuric acid solution produces a yellow to brown color. 
Nitrobenzol containing a trace of nitrothiophen colors the alkaloid violet 
red. 

In the general scheme of alkaloidal analysis cytisin will be found in 
the fraction obtained by shaking out the alkaline solution with ether, 
though probably the greater portion will be subsequently removed on 
shaking out with chloroform. 

DELPHINIUM BASES 

Extracts of the seeds of Delphinium staphisagria (Ranunculacese), 
stavescare from Southern Europe, and of D. consolida, the common field 
larkspur of the United States, are employed to a limited extent as medici- 
nal agents. Another species, D. urceolatum, growing in the United 
States, is sometimes substituted for D. consolida. Stavescare is a power- 
ful emetic, narcotic, carthartic, and vermifuge as well as a parasiticide. 
It is prescribed in various disorders of the urinary tract, including tem- 
porary enlargement or irritation of the prostate, and may therefore be 
suspected in any remedy recommended for such ailments. It is used 
externally for eczema and for destroying lice and itch mite. 

Larkspur is used principally as a parasiticide for destroying crab- 
lice and vermin infecting the scalp. 

The bases of D. staphisagria which have been definitely established 
include delphinin, delphisin, and probably delphinoidin. D. consolida 
may contain some or all of these bases. Keller 1 obtained a crystalline 
alkaloid from the latter drug, which w T as not identical physiologically 
with delphinin. He also determined that the commercial delphinin is 
a mixture. 

The alkaloids may be extracted from an alkaline solution by ether, 
1 Arch. Pharm., 248, 463. 



ALKALOIDS DERIVED FROM PYRIDIN 99 

and on concentrating and allowing to stand the delphinin crystallizes 
first in rhombic crystals melting 191-198°; on further evaporation delphisin 
separates, and then dilphinoidin may be thrown out by adding petroleum 
ether. 

The pure bases do not give characteristic color tests. Reactions have 
been reported which were obtained with impure residues: thus sulphuric 
acid containing malic acid produces an orange color, changing gradually 
to red and finally dirty blue; sulphuric acid and bromine water a violet 
color; and sulphuric acid and sugar a brownish yellow changing to green 
on dilution with water. 

BASE FROM DUBOISIA HOPWOODH 

Duboisia hopwoodii (Solanacese), growing in central Australia, is 
another of those plants like coca and kola which furnishes a drug having 
stimulating properties enabling its devotees to perform much labor and 
go long journeys with but little food. The drug is a fine powder composed 
of the leaves and twigs gathered while the flower is in bloom and put up 
in various forms of circular mats about 6 in. in diameter. The drug has 
not been exported medicinally to any extent, but attention is called to 
it owing to its local use, which may lead to its adoption by the pharmaceu- 
tical profession after the manner in which coca and kola were first exploited. 

The drug contains a volatile alkaloid which has been called piturin, 
after the local name of the drug Pituri. Investigation by different workers 
has been conflicting, some claiming it to be identical with nicotin, others 
denying this similarity. Senft states that it differs from nicotin in its 
reactions with platinic, gold, and meruric chlorides, and with iodine. 
Its aqueous solution does not become turbid on heating, which distin- 
guishes it from coniin, 



CHAPTER V 
ALKALOIDS DERIVED FROM PYRROLIDIN 

THE SOLANUM ALKALOIDS 

Atropin, C17H23NO3 
Hyoscyamin, C17H23NO3 
Scopolamin, C17H21NO4. 

In addition to the above three it has been recorded that the drugs 
bearing these alkaloids contain small amounts of atropamin, belladonin, 
mandragorin and pseudohyoscyamin. However, their existence is doubt- 
ful, the literature on the subject is discrepant and it appears from more 
extended research that they were mistaken for mixtures in varying pro- 
portions of the three alkaloids. Hyoscin, which was formerly reported 
as a naturally occurring constituent of henbane, has now been virtually 
relegated to oblivion. Daturin, now called atropin, was probably a 
mixture of atropin and hyoscyamin; duboisin is now classed as hyos- 
cyamin by some and as scopolamin by others. 

This group includes also the artificially prepared homatropin, 
C10H21NO3, having the composition of a lower homologue of atropin as 
well as other synthetic derivatives of tropein, which are used more or 
less in medicine. 

The following plants of the Solanacese have been found to contain 
these alkaloids; Atropa belladonna, Deadly Nightshade; Hyoscyamus 
niger, Henbane; H. albus, H. muticus; Datura stramonium, Thorn- 
apple or Jamestown Weed, and other species of Datura; Duboisia myopo- 
roides, Corkwood Elm; Scopolia atropoides or carniolica; S. japonica, 
Japanese Belladonna; Mandragora officinarum, European Mandrake, 
Anisodus luridus, and according to some authors in Lactuca sativa and 
virosa (Compositse) . All parts of the plants contain the alkaloids. The 
relative proportions of the alkaloids have never been satisfactorily deter- 
mined owing to the ease with which hyoscyamin is converted to atropin, 
but the consensus of jopinion seems to be that atropin predominates in 
belladonna, though Rusby states that over one-half the total alkaloid 
in the commercial root is hyoscyamin according to Gilpin and Langdon, 
while hyoscyamin and scopolamin are present in greater amount in hen- 

100 



ALKALOIDS DERIVED FROM PYRROLIDIN 101 

bane. Pseudohyoscyamin was reported by Merck in Duboisia myopo- 
roides, but has never been observed in any other species. 

The young roots of belladonna are reported to contain scarcely any 
atropin, only hyoscyamin, while the ripe fruit on analysis contains only 
atropin. The alkaloidal content varies with the period of their growth. 
Gunther has shown that the fresh plants contain the alkaloids in the 
following proportions expressed in parts per 1000. 

Atropa belladonna, leaves 2.0; stems 0.4: unripe fruit 1.9; ripe fruit 
2.1; seeds 3.3; root 0.6. 

Datura stramonium, leaves 0.7; stems 0.2; seeds 2.5; root 0.2. 

The drugs used medicinally when ready for market contain the alka- 
loids in the following percentages: 

Atropa belladonna 0.2 to 1.0 per cent, the average being 0.55 to 0.60. 
The Pharmacopoeia requiring the leaves test not less than 0.30 per cent 
and the root 0.45 per cent. 

Hyoscyamus .00 to 0.15 per cent, the standard requirement being 
.065 per cent. 

Scopola somewhat greater than the amount present in belladonna 
root, the old standard being 0.5 per cent, but the drug is no longer official. 

Stramonium 0.2 to 0.4 per cent, the Pharmacopoeia requiring not 
less than 0.25 per cent. 

The crude belladonna leaves have been found mixed with those of 
Scopola and sometimes with a species of Phytolacca; Belladonna root 
has been largely adulterated with Phytolacca root and the literature 
records the use of Medicago root and Scopola; Hyoscyamus leaves have 
been adulterated with Stramonium; and Stramonium has been found 
adulterated with other species of Datura and also with a spurious Stra- 
monium called " French cultivated." Hyoscyamus muticus is often 
offered for import as true H. niger. 

The substitution of one drug for another or the use of an adulterant 
may be detected microscopically in powdered products ; in liquid prepar- 
ations the analyst's difficulties become greater, especially where one vari- 
ety of the Solanaceae has been substituted for another, though the use of 
products containing Phytolacca should be more readily detected owing 
to the entirely different nature of the ingredients in the latter. 

Extract of belladonna will be found usually in combination with other 
drugs, and is employed as an anodyne, a suppressant of secretions, for 
whooping cough, croup, chronic constipation, incontinence of urine, nar- 
cotic poisoning, etc. It is an antigalactogogue, and is a component of 
many different kinds of plasters. The alkaloid has a wide use as a mydri- 
atic. The drug or its alkaloids are chiefly administered in the form of 
pills and tablets and a large number of different formulge have been evolved. 

Scopola is used as an anodyne. Hyoscyamus is a deliriant narcotic, 



102 ALKALOIDAL DRUGS 

anodyne, antispasmodic, and hypnotic, and is employed chiefly to relieve 
pain and quite nervous excitement. It is used in asthma, whooping 
cough, functional palpitation of the heart, chorea, hypochondriasis, 
mania, etc., and also as a sedative in place of opium. 

Stramonium is a powerful narcotic, antispasmodic, and anodyne, and 
is used similarly to belladonna. It is employed in the powered form as 
a remedy for asthma. 

The extract of Duboisia is used for the same purposes as belladonna, 
but is claimed to be less of a cerebral excitant and more calmative and 
hypnotic. 

Mandragora is stated by Rusby to be the Mandrake of the Bible; 
it has properties similar to the other drugs of this family, but will seldom 
if ever be met with in the course of analytical work. 

From the above resume of the uses of the drugs and alkaloids under 
consideration an idea may be formed as to the different remedies in which 
they might be expected 

Some of the more important combinations of belladonna and atropin 
include the following: 

Pills. Belladonna and aloes or aloin with Nux Vomica or strychnin 
to which will often be added Capsicum, ginger, Cascara, ipecac, colocynth, 
and calomel, one or more in different combinations. In some instances 
Podophyllum will take the place of the Nux Vomica and again the aloes 
will be omitted. Belladonna, podophyllum and Physostigma are used 
together; and belladonna is combined with phosphorus. As a compo- 
nent of neuralgic and idiopathic remedies it occurs with Hyoscyamus, 
Ignatia, Opium, Conium, Stramonium, Aconite and Cannabis sativa; 
with salicin, zinc oxide, pepsin and Hydrastis it is used for night sweats. 
Pills of morphin and atropin are used, and atropin has also been combined 
with quinin, arsenic, and gentian. 

Tablet triturates will be found containing many of the above men- 
tioned mixtures of aloin, belladonna, strychnin, Cascara, Podophyllum, 
ipecac, etc. Bronchitis mixtures are found containing belladonna, acon- 
ite, Bryonia, sulphurated antimony and potassium bichromate, or bella- 
donna, opium, ipecac and quinin. Atropin, morphin, camphor, and 
quinin are used for coryza. An infant's cough formula contains ammo- 
nium chloride, ipecac, opium, Glycyrrhiza, and belladonna. A standard 
formula for follicular tonsillitis contains belladonna, aconite, Bryonia, 
mercuric iodide, morphin, sodium salicylate, and methyl salicylate. It 
is used with nitroglycerin, Strophanthus, and Digitalis in heart tonics; 
it is combined with picrotoxin alone; rhinitis formulas contain bella- 
donna, camphor, and quinin; throat tablets contain benzoic acid, cam- 
phorated opium, Glycyrrhiza and belladonna; and a formula is reported 
for sciatica containing belladonna, aconite, Colchicum and Cimicifuga. 



ALKALOIDS DERIVED FROM PYRROLIDIN 103 

In the formulas of compressed, sugar-coated and chocolate-coated tab- 
lets belladonna or atropin take part in a legion of mixtures, many are 
repetitions of those above given, but to these may be added the following: 
with potassium iodide, potassium arsenite, Lobelia, and opium in asth- 
matic compounds; with sanguinarin nitrate, morphin, antimony, and 
potassium tartrate, aconite, ipecac, and tar in a cough mixture; with boric 
acid, benzoic acid, potassium bicarbonate, buchu, Triticum, corn silk, 
Hydrangea in mixtures for cystitis; with gold and sodium chloride, strych- 
nin, nitroglycerin, Digitalis, and Capsicum for dipsomania; with lupulin, 
Scutellaria, ergotin and zinc bromide; with saw palmetto, cantharides 
and cornsilk; with terpin hydrate, wild cherry, guaiac, and camphorated 
opium; with antipyrin ; zinc oxide, and Castanea for whooping cough. 

Ophthalmic tablets of atropin sulphate and of homatropin hydro- 
bromate are used considerably.. Hypodermatic tablets contain atropin 
sulphate alone and combined with morphin sulphate, and there is a local 
anesthetic formula containing atropin sulphate, morphin sulphate, and 
cocain hydrochlorate. 

Elixirs are sold to a limited extent containing aloin, belladonna, strych- 
nin and Podophyllum; and a tonic compound sold in capsule form con- 
sists of atropin, beechwood creosote, strychnin, arsenous acid, and cod 
liver oil. 

Belladonna ointment usually has a base of benzoinated lard. Bella- 
donna plasters contain lead oleate, petrolatum, rubber, and sometimes 
soap, colophony and Burgundy pitch in the base. 

Hyoscyamus, in the form of the drug extract, enters into a great vari- 
ety of different combinations, many of which resemble to a greater or 
less extent those in which belladonna functionates and, consequently they 
will not be repeated here. Among the pills and tablets attention will be 
directed to those which have been found to differ from the formulas given 
above under belladonna. Hyoscyamus with camphor, Capsicum and 
morphin in anodyne products; with Podophyllum, colocynth, Cascara, 
Juglans, Nux Vomica, gentian and Apocynum, also with jalap, leptandra, 
aloin, gamboge and Capsicum in laxative remedies; in the compound 
vegetable cathartic of the National Formulary. With camphor, valerian 
and Opium; with irisin and strychnin; with musk root, valerian, and 
Cannabis sativa in sedative mixtures; with ammonium chloride, Gly- 
cyrrhiza, Tolu, cubeb, senega, and ipecac in bronchial remedies; with 
calomel, rhubarb, and colocynth; with morphin hydrochloride, Cannabis 
sativa, nitroglycerin, Capsicum, and peppermint in chlorodyne; with 
ferrous lactate, cinchonin sulphate, arsenous acid, and strychnin; with 
sodium bromide, acetanilid, and digitalin in hypnotic compounds; with 
acetanilid, camphor monobromated, sodium salicylate, and Gelsemium for 
migraine; with sodium bromide, caffein, acetanilid, and morphin for 



104 ALKALOIDAL DRUGS 

neuralgic headache; and with opium, Hamamelis, tannic acid, thymol 
helonias, salicylic acid, boric acid, alum, and eucalyptol for topical use 
in leucorrhea. 

Scopolamin, hydrobramate (Hyosin.) hyoscyamin, and Hyoscyamus 
extract individually occur in tablet triturates, and the alkaloidal salts 
occur in hypodermatic tablets. 

The liquid products are not numerous and are usually elixirs; thus 
we have a formula embracing chloral, potassium bromide, Cannabis 
sativa, and Hyoscyamus, and another with the same ingredients includ- 
ing morphin; again a product of the nerve tonic type composed of skull- 
cap, hops, Hyoscyamus, valerian, ammonium bromide, and coca. 

Scopola resembles belladonna very closely in medicinal and physio- 
logical action but is not used to the same extent. It has been largely 
employed in the manufacture of plasters and is also the source of most 
of the commercial scopolamin (hyoscin) salts. 

Stramonium occurs in the pill formula mentioned under belladonna 
which is used for neuralgia idiopathic, but its greatest field is in asthma 
powders, pastilles, and cigarettes. In powders it occurs with Grindelia 
robusta, Pilocarpus, Eucalyptus, coca, Digitalis, cubeb, cascarilla, and 
potassium nitrate; in pastilles with benzoin, Pilocarpus, charcoal, and 
potassium nitrate; and in cigarettes with cascarilla, Lobelia, and mul- 
lein. 

Treatments for the drug and liquor habits often contam scopolamin, 
and with this alkaloid may occur morphin sulphate heroin, cafTein, spar- 
tein, Pilocarpus, and carbolic acid, 

Atropin. Tropyl-tropin. Inactive Atropin. Daturin. 
H 
H 2 C C CH 2 CH 2 OH 

I \ I 

N • CH 3 CH • O • CO CH— C 6 H 5 

I / 

H2C C CH2 

H 

Pure atropin forms tufts or groups of colorless or white lustrous needles 
or acicular prisms, crystallizing in this way from alcohol or chloroform. 
In commerce it often occurs as a crystalline or nearly amorphous yellowish 
powder, and the commercial article usually contains hyoscyamin, from 
which it may be freed by treatment with dilute alcoholic alkali at a tem- 
perature of 110° for five or six hours, until there is no further change in 
its optical activity. Pure atropin is without action on polarized light. 
Hyoscyamin is its stereoisomer, being the laevo modification, while atropin 
is the racemic form. The separation of the latter has not as yet been 
effected, although the constituents have apparently been synthesized. 



ALKALOIDS DERIVED FROM PYRROLIDIN 105 

It is a strong poison and is used largely in medicine on account of its 
mydriatic and other properties. Its property of dilating the pupil of the 
eye is used to confirm its presence. The pure alkaloid melts 115-116° C, 
while the commercial substance containing more or less hyoscyamin, melts 
from 104 to 114°. 

It is sublimable, almost unchanged; and gradually loses weight when 
heated to 100° C. It is somewhat volatile with steam. 

It is readily soluble in alcohol, chloroform, carbon tetrachloride, and 
toluol, less so in ether and only slightly soluble in petroleum ether and 
carbon bisulphide. The proportions given in the literature for its solu- 
bility vary over wide limits. 

It is not removed by immiscible solvents from solutions acidulated 
with mineral acids, but from solutions made acid by tartaric acid it is 
stated that ether and chloroform will remove it. 

Its aqueous solution is alkaline to litmus and reddens phenolphthalein, 
the latter property being almost exclusively characteristic of atropin and 
its isomers among the other alkaloids. 

Atropin is precipitated by Mayer's reagent, iodin in potassium iodide, 
potassium-bismuthous iodide, potassium-cadmium iodide, phospho-molyb- 
dic and phosphotungstic acids, tannic acid; alcoholic picric acid yields 
a precipitate having a characteristic form, valuable in microscopic detec- 
tion, and a saturated solution of bromin in hydrobromic acid or alcohol 
produces a precipitate in dilute solutions, amorphous at first, but soon 
becoming crystalline and highly characteristic. No precipitates are given 
with potassium iodide, sulphocyanide, ferro, and ferri-cyanide, nor chro- 
mate. 

Gold chloride produces a very characteristic precipitate with atropin, 
in fact the gold chloride compound furnishes the best test for distinguish- 
ing between this alkaloid and the other solanum bases. It is thrown down 
from dilute solutions as an amorphous or oily precipitate which gradually 
becomes crystalline, and has a well-defined form under the microscope. 
It melts under hot water and is deposited from its solution in boiling 
water acidulated with Irydrochloric acid in minute crystals which are luster- 
less after drying at 80° and melt at 135-138°. Hyoscyamin aurochlo- 
ride retains its luster when dry and melts 160-162°; scopolamin auro- 
chloride melts 198-199°, and homatropin aurochloride 142-145°. 

Atropin picrate melting 174.5-175° C. is prepared by adding a few 
mils of a saturated solution of picric acid to a fairly concentrated solu- 
tion of the alkaloid in dilute hydrochloric acid. After washing with 
water, the precipitate should be recrystallized from dilute acetone. 

Bromine water in aqueous hydrobromic acid produces characteristic 
crystals even in very dilute solution. These crystals when viewed under 
the microscope furnish an excellent test of identity. 



106 ALKALOIDAL DRUGS 

With platinic chloride atropin gives a powdery, resinous precipitate 
which balls together and is very soluble in hydrochloric acid. Hence 
from solutions acidulated with hydrochloric acid it is not thrown down 
by platinic chloride, a reaction which distinguishes atropin from the great 
majority of alkaloids and which may be used to a certain extent for sepa- 
rating mixtures. On evaporating a dilute solution of the platinum salt 
it separates in monochinic crystals which melt with decomposition at 
207-208°. 

Atropin sulphate is the form in which it usually appears commercially, 
though this product is rarely chemically pure, containing a trace of hyos- 
cyamin. 

The melting-point of this body is given variously from 180 to 191° C. 
Beilstein states that the commercial article containing hyoscyamin melts 
at 188-191° and the pure salt free of hyoscyamin at 181-183°. 

Atropin and allied bases respond to a number of interesting color and 
odor tests. Vitali's color reaction is probably the most sensitive and 
furnishes a very good indication of the presence of these alkaloids. It 
is easy of application, the alkaloidal residue being first evaporated with 
concentrated nitric acid, and when dry and cool the product treated with 
a few drops of strong alcoholic potash, when in the presence of solanum 
bases a beautiful purple color appears going through the entire liquid 
and gradually disappearing through a cherry red. The purple color may 
be again produced by evaporating with nitric acid and treating with alco- 
holic potash. While this reaction is of great value as an indication of the 
presence of atropin, it cannot be considered as conclusive proof, as other 
alkaloids and alkaloidal residues obtained from medicinal products will 
give the same or very similar test, so similar in fact that when working 
with small amounts, the distinguishing features are not apparent. Thus 
strychnin when similarly treated gives a purple color which is permanent, 
and gradually becomes brownish; yohimbin and alkaloidal residues from 
yohimbe bark give a purple color, the color being quite fleeting and most 
prominent on the edges and in thin layers and soon changing to brown; 
alkaloidal residues obtained from coca leaf will in some instances give a 
purple color, but pure cocain will not. It is claimed that veratrin will 
give the same test as atropin, but the writer has never been able to con- 
firm the statement; commercial veratrin gives a fleeting pink color when 
nitric acid is added, but no purple color developed on subsequently add- 
ing alcoholic potash to the evaporated residue ; alkaloidal residues obtained 
from Veratrum viride acted in the same way and in both cases there 
was noted a strong odor of old beef. Homatropin does not respond to 
Vitali's test. 

Gerrard has described a reaction with mercuric chloride which Allen 
epitomizes as follows: 0.1 grain of the free alkaloid (extracted from a 



ALKALOIDS DERIVED FROM PYRROLIDIN 107 

salt by ammonia and chloroform) is placed on a watch glass or in a test 
tube and 20 drops of a 2 per cent solution of mercuric chloride in 50 per 
cent alcohol gradually added. A red coloration is yielded at once with 
atropin. Hyoscyamin at first becomes yellow, then darkens a little, and 
finally, on heating, a well-marked red precipitate is formed. If a large 
excess of hyoscyamin be used, merely a yellow precipitate is formed, while 
with a large excess of the reagent no precipitation occurs. Homatropin 
also yields a red precipitate under the conditions of the test; but hyoscin 
(scopolamin) gives neither a red nor a yellow coloration or precipitate, 
and hence is sharply distinguished from the other tropeins. Gerrard 
found no red or yellow precipitate to be produced by strychnin, brucin, 
morphin, codein, veratrin, aconitin, coniin, gelsemin, caffein, cinchonin, 
cinchonidin, quinin, or quinidin; though most of these bodies gave white 
precipitates, which, in the cases of codein and morphin, became pale 
yellow on heating. Cocain is also claimed to give a white precipitate (only 
appearing in strong solutions and soluble on warming) and scoparin a 
yellow precipitate. 

Atropin and the solanum bases yield a leaf-green to olive-green color 
when treated with a mixture of 1 volume of perhydrol and 10 volumes 
of concentrated sulphuric acid. Cocain gives an emerald-green shade. 

Atropin when warmed with sulphuric acid until liquid is brown and 
then treated with a drop or two of water gives off odors of rose, orange 
flower, and melilot, and the addition of potassium bichromate will change 
this to the odor of bitter almonds. 

Atropin evolves ammonia when heated with caustic alkalies. On 
heating with chromic-acid mixture benzoic acid is formed. 

The physiological test is very delicate and may be performed best 
on a cat's eye with a dilute neutral aqueous solution of the alkaloid or 
of the alkaloidal residue to be tested. No alcohol nor free acids should 
be present, and excess of neutral salts are to be avoided, the specimen 
being best prepared by evaporating either a hydrochloric or acetic solu- 
tion until most of the acid has disappeared, then cautiously neutralizing 
with sodium bicarbonate, and finally filtering. Cocain also produces 
mydriasis, and coniin, nicotin, aconitin, and gelseminin are stated to have 
a more or less similar effect on the pupil. 

From the above description of atropin it will be seen that for forensic 
work it is necessary for the analyst to consider more than one reaction 
when reporting an alkaloid suspected of being atropin. If sufficient 
quantity is obtainable the melting-point of a positively pure residue 
furnishes excellent proof when corroborated by the melting-points of the 
aurochloride and picrate, the microscopic appearance of these salts and 
the physiological test. The presence of cocain would be indicated by 
the marked odor of ethyl benzoate when the Vitali reaction was performed. 



;108 ALKALOIDAL DRUGS 

Both dextro- and laevoatropin have been prepared; they have a melt- 
ing-point of 110-111° and the aurochlorides melt 146-147°. 

HYOSCYAMIN 

This alkaloid forms lustrous needles melting 108.5° C. It behaves 
similarly to atropin both chemically and physiologically. The optical 
activity, melting-point of the aurochloride and characteristic form of the 
picrate under the microscope serve to distinguish it from the other sola- 
num alkaloids. 

In alcoholic solutions its rotation is [a]*— 20.3° or —21°. 

The aurochloride does not melt in boiling water, the scales are lustrous 
and have a melting-point of 159-162° when pure at 165°. The picrate 
melts 161-164°. 

The platinum salt does not separate from dilute acid solution, but on 
evaporation of an aqueous solution it may be obtained in orange prisms 
melting with decomposition at 206° C. 

Hyoscyamin may be converted to atropin by heating for several hours 
at 110° or by standing for several hours in alcohol and sodium hydrate. 

Dehydrating agents convert it to atropamin and belladonin. On 
hydrolysis with barium hydrate or hydrochloric acid it gives tropin and 
tropic acid. 

On saponifying hyoscyamin with hot water Merck obtained tropin and 
active laevorotatory tropic acid. The laevo-tropic acid is the direct saponi- 
fication product of hyoscyamin; if the saponification is conducted in an 
acid or alkaline solution the active acid is converted into the racemic form. 
Hyoscyamin may thus be considered the laevo-modification of atropin. 
However, an experiment made in 1889 by Ladenburg and Hunt would 
seem to indicate that the relation existing between the two alkaloids is not 
so simple as we might suppose. They separated inactive tropic acid 
through its quinin salt into two active forms. The lsevo-acid thus pre- 
pared should be identical with that obtained by Merck, since in tropic 
acid there is only one asymmetric carbon atom. Ladenburg and Hunt 
on uniting this laevo-acid with inactive tropin obtained a lsevo-tropin, 
which although similar to hyoscyamin, was apparently not identical with 
it. From this one might conclude that the stereoisomeris mof the two alka- 
loids is not situated alone in the acid part of the molecule — the tropic 
acid — but also in the basic part — the tropin. 

According to the investigations of Gadamer, however, the tropin in 
both atropin and hyoscyamin is inactive, and the only difference between 
the two alkaloids lies in the inactivity in one case and the activity in the 
other of the tropic acid radicle. Recently Amenomiya states that he has 
obtained dextro- and laevo-hyoscyamin by the union of d- and Z-tropic 
acids with tropin. 



ALKALOIDS DERIVED FROM PYRROLIDIN 109 

Z-SCOPOLAMIN 
Inactive scopolein ester of laevo-tropic acid 

Scopolamin crystallizes with one molecule of water and has a melting- 
point of 56-57° C. It is generally seen in the amorphous condition. 

Chemically and physiologically it behaves similarly to the other alka- 
loids of this group. 

It is somewhat more easily soluble in water than atropin and hyos- 
cyamin and dissolves readily in alcohol, ether, and chloroform. 

Its rotation in absolute alcohol is reported as being [a] d — 13° and —18° 
and in water —28°. Pictet states that the hydrobromide rotates — 25° 43'. 

The aurochloride melts with decomposition at 198-199° C. and Allen 
states that in the anhydrous condition it melts 214° C. The picrate has 
a melting-point 187-188°. 

The crystalline salts are characteristic in the microscopic form. 

On hydrolysis, scopolamin yields tropic acid and oscin or scopolin, and 
it is slowly hydrolyzed in aqueous solution. 

By the action of alkalies or alkaline carbonates scopolamin may oe 
converted into an inactive ciystalline derivative having one molecule of 
water and melting at 56° C, the gold chloride of which melts at 201° or 
208°. In commercial scopolamin hydrobromid" Hesse found an inactive 
alkaloid called atroscin and which is the dihydrate of scopolamin. It 
melts at 38-38°. Atroscin is also found in the roots of Scopolia atropoides. 
It may be formed when inactive scopolamin is dried over sulphuric acid 
and then heated to 80° C, the residue dissolved in absolute alcohol, and 
a few drops of water added. 

The anhydrous atroscin melts at 82-83° according to Pictet. 

Atroscin can be converted into isoscopolamin by inoculating an atro- 
scin solution with a crystal of isoscopolamin and the reverse transfor- 
mation has been effected. Further atroscin may be changed to isoscopol- 
amin if the hydrobromide of the former is prepared, the base again freed 
from this and crystallized from an aqueous solution of definite concen- 
tration at 0°. Both atroscin and isoscopolamin are decomposed by alka- 
lies into tropic acid and scopolin. 

In order that the relations of these various scopolamin derivatives to 
one another may be more clearly represented Wolffenstein proposes the 
following nomenclature: 

The inactive anhydrous alkaloid, C17H21NO4, ^'-scopolamin. 

The inactive alkaloid containing one molecule of water (isoscopol- 
amin), i-scopolamin monohydrate. 

The inactive alkaloid containing two molecules of water (atroscin), 
z-scopolamin dihydrate. 



110 ALKALOID AL DRUGS 



DERIVATIVES AND PRODUCTS OF HYDROLYSIS 

Atropamin, G7H21NO2, is formed when atropin or hyoscyamin are 
dehydrated with sulphuric acid or the anhydrides of phosphoric acid, 
acetic acid, etc. It crystallizes from ether in prisms melting at 60-62°, 
readily soluble in alcohol, ether, and chloroform, but only slightly soluble 
in water and petroleum ether. It is inactive to polarized heat and has 
no mydriatic effect. On being heated it undergoes a molecular rearrange- 
ment to form its isomer belladonin. Also when warmed with barium 
hydroxide or with hydrochloric acid there first occurs the same rearrange- 
ment, but this is then followed by saponification to atropic acid, CgNgO, 
and tropin. This reaction lus been reversed. 

On hydrolyzing the solanum bas:s we obtain the following: 
Atropin and hyoscyamin yield tropic acid, CgN^oOs, and tropin, 

C 8 H 15 NO. 
Scopolamin yields tropic acid and scopolin, C8H13NO2. 

Allen states that the preferable method for effecting the saponification 
of the tropeins is to heat the alkaloid with saturated baryta water to 60 
or 80° for a few hours Carbon dioxide is n xt passed through the liquid 
until a drop ceases to give a pink color with phenolphthalein. The liquid 
is then filtered and the filtrate acidulated with hydrochloric acid and twice 
shaken with ether. The ether is separated and on evaporation yields the 
acid product of hydrolysis; on treating the aqueous layer with caustic 
alkali in excess and agitating with ether the basic product is extracted 
and may be recovered by separating and evaporating the ether. 

When the hydrolysis is effected by an acid, especially concentrated 
hydrochloric acid, the tropic acid loses the elements of water and atropic 
acid results, and at high temperatures this is more or less changed into 
its polymers alpha- and beta-isatropic acid, C18H16O2. 

Tropic acid, C 6 H 5 CH(CH 2 OH)COOH 

alpha-phenyl-bet a-hy droxypropi onic acid. 

The acid crystallizes from hot water in needles or slender prisms and 
on the spontaneous evaporation of its aqueous solution in tablets which 
melt 117-118°. It is not volatile without decomposition. It is some- 
what soluble in water and dissolves more readily in alcohol and ether. 
It is optically inactive and without any particular physiological action. 
When heated with a dilute solution of potassium permanganate benzal- 
dehyde is given off, and on further treatment benzoic acid is produced. 

The formula for tropic acid contains an asymetric carbon atom and 
it should be possible to separate the inactive acid into two active modi- 
fications. This separation was effected as previously mentioned by Laden- 
burg and Hunt by crystallizing the quinin salts. Dextro-tropic acid 
melts 127-128° and hevo-tropic acid 123-126°. 



ALKALOIDS DERIVED FROM PYRROLIDIN 111 



Atropic Acid, C 6 H 5 C = CH 2 COOH 

alpha-phenylacrylic acid 

Atropic acid is isomeric with cinnamic acid, but differs from it by its 
solubility in water (1-692 at 19°, Allen), by its lower melting-point 106- 
107°, and in not being precipitated by manganese salts from its neutral 
solutions. It is volatile with steam and boils with partial decomposi- 
tion at 267° C. It is very soluble in carbon bisulphide. Chromic acid 
oxidizes it to benzoic acid, and when fused with caustic potash it yields 
formic and phenylacetic acids. Sodium amalgam reduces it to alpha- 
phenyl propionic acid and bromin water converts it into brom-phenyl- 
propionic acid, 

Isatropic Acid, Ci 8 Hi60 4 

This acid is polymeric with atropic acid and is always formed together 
with that acid and tropic acid when atropin is heated with hydrochloric 
acid. It is always formed when atropic acid is crystallized from hot 
water and especially if the solution has been boiled for some time. 

It exists in a number of isomeric modifications, the alpha acid melting 
at 237° and the beta at 206°. The gamma and delta acids are called 
truxillic acids, and are described under the products of hydrolysis of the 
coca alkaloids. 

Tropin 

H 

H2C C CH2 

I \ 

N-CHs CHOH 

I / 

H 2 C C CH 2 

H 

Tropin crystallizes from absolute ether in rhombic plates melting 61- 
63° and boiling 229-233°. It is hygroscopic, readily soluble in water, 
alcohol, and ether. It is without action on polarized light, has no mydri- 
atic effect, and is much less poisonous than the alkaloids derived from it. 
It is a strong base, has an alkaline reaction, and forms well-crystallized 
salts. 

The platinum chloride compound forms orange-red monoclinic prisms, 
easily soluble in warm water, insoluble in alcohol, and melting with decom- 
position at 198-200°. The aurochloride forms yellow plates melting 210- 
212°. The picrate is a yellow precipitate crystallizing from hot water 
in yellow needles, decomposing without melting at 275°. 



112 ALKALOIDAL DRUGS 

Scopolin (Oscin), C 8 Hi 3 N0 2 

Scopolin crystallizes from petroleum ether or chloroform in prisms, 
melting at 110°, and boils at 241-243°. It is easily soluble in water and 
alcohol. It is a tertiary base and optically inactive. It appears to be 
related to tropin in the sense that a CH2 group of the latter is replaced 
by a CO group; it does not, however, give any reaction for ketone. 

It is possible to introduce different acid radicles into the tropin and 
scopolin molecule, thus forming a large number of derivatives known as 
tropeins and scopoleins. Thus we have products known as benzoyltro- 
pein; phenylacetropein, cinnamyltropein ; salicyltropein ; phenylglyco- 
lytropein or homatropin; acetylscopolein, benzoylscopolein, cinnamyl- 
scopolein, and many others, whose properties have been studied and 
constants recorded^ 

Homatropin, Ci 6 H 2 iN0 3 

C 8 Hi 4 N0 -C0CH(0H)C 6 H 5 

This product usually occurs in the form of its hydrobromide. It is 
prepared artificially and is the tropylester of phenylgly colic or mandelic 
acid. The base crystallizes from ether in glassy prisms, melting 92-98° 
according to different authors. Its mydriatic effect is as marked as that 
of atropin for about twelve to twenty-four hours and then subsides while 
the effect of atropin will often last a week. It is claimed to be less toxic. 

It is readily soluble in ether and chloroform. It is claimed to act 
similarly to atropin when tested with alcoholic mercuric chloride, but it 
does not give a purple color when tested by Vitali's reaction. It yields 
a precipitate with Mayer's reagent and a crystalline precipitate with 
picric acid, melting 180,5-181.5°, The aurochloride melts 142-145°. 

Euscopol 

This product is claimed to be inactive scopolamin hydrobromide, dif- 
fering from the ordinary scopolamin hydrobromide which is stated by the 
claimants to be a mixture of active and inactive salts. 

Distinguishing Tests. — From the descriptions of the individual mem- 
bers of this group the chemist will have no difficulty in distinguishing 
between the alkaloids. Their melting-points are well defined, their auro- 
chlorides and picrates furnish a ready means for their identification, and 
their crystalline salts are characteristic under the microscope. 

Allen states that Ladenburg employs the aurochlorides to separate the 
tropeins from each other. The atropin salt is the most insoluble and in 
fractional precipitation is thrown down first while the hyoscyamin salt 
is the most soluble. The alkaloids may be recovered by decomposing the 



ALKALOIDS DERIVED FROM PYRROLIDIN 113 

aurochlorides with hydrogen sulphide, adding ammonia to the filtrate and 
agitating with chloroform and ether. 

Formulas where these alkaloids or their salts in the pure form play a 
part seldom if ever contain more than one individual, so that the chemist 
will have no occasion to effect their separation. He may, however, be 
called upon to separate atropin from strychnin, morphin, cocain, and pos- 
sibly quinin. 

We have seen that there are a great variety of mixtures in which the 
drugs belladonna, Hyoscyamus, scopola and stramonium are used, but 
here again the number of alkaloids from which the solanum bases must 
be distinguished are not numerous. Many of the ingredients in the mix- 
tures will be removable* from acid solution with immiscible solvents and 
others may be precipitated by lead salts. If morphin is suspected the 
product should be treated with sodium hydrate before shaking out with 
immiscible solvents from alkaline solution. 

The ether residue obtained by shaking out an alkaline solution should 
be the first one examined for this group as petroleum ether extracts but 
little atropin, most of the cocain if present going into this portion. The 
Vitali reaction should be tried on a portion and if no purple color is obtained 
on adding alcoholic potash there is no need of further testing, except to 
guard against overlooking homatropin. Antipyrin will interfere with this 
test and will be apparent if present when the mixture is evaporated with 
nitric acid, a deep purple developing at once and preventing any subsequent 
reaction with alcoholic potash ; and it should be remembered that a whoop- 
ing-cough mixture occurs containing both antipyrin and belladonna. 

Even if on adding alcoholic potash a purple color develops, one is not 
absolutely certain that atropin, hyoscyamin, or scopolamin are present, 
as strychnin gives the same color, impure coca bases do likewise, and the 
alkaloids of yohimbe, exploited now for the same purpose as strychnin, 
give a purple tint. - If cocain is present it would be apparent by the odor 
of ethyl benzoate, and a test with bichromate-sulphuric acid would show 
whether strychnin existed. If Vitali's reaction is performed with the 
chloroform residue in the presence of brucin, it is difficult if not impossible 
to obtain any purple color owing to the deep shades produced by nitric 
acid on brucin. 

Cocain may be separated partially from atropin, since it is so readily 
soluble in petroleum ether, two shakings being usually sufficient to remove 
it, while most of the atropin will remain to go later into the ether and 
chloroform fractions. Strychnin may be separated from the solanum 
bases by precipitating it out with platinic chloride in the presence of dilute 
hydrochloric acid, filtering, and then shaking out the tropeins from alka- 
line solution. Morphin, of course, will not be removed from a solution 
alkaline with sodium hydrate, but with opium present one must look for 



114 ALKALOIDAL DRUGS 

codein, which fortunately does not interfere with Vitali's reaction, and no 
trouble need be anticipated from the presence of ipecac and Physostigma 
alkaloids or quinin. 

If it is possible to obtain sufficient of the gold salt and picrate in the 
pure condition to obtain melting-points, the analyst has an excellent con- 
firmatory test, and the microscopic appearance of the crystalline salts is 
conclusive. 

The question is sometimes asked, How can you distinguish between 
belladonna and scopola, the latter drug often being used in place of bella- 
donna? If the quantity of alkaloidal residue obtainable is in sufficient 
quantity, there ought to be no great difficulty in answering the question, 
for the presence of a considerable amount of scopolamin would be a strong 
proof that scopola had been used. The separation may be effected by 
the fractional precipitation of the gold salts and by a method recently 
described where the hyoscyamin is first thrown out by sodium bicar- 
bonate and after its removal the scopolamin is separated by potassium 
carbonate; though on the efficiency of this latter method the writer is 
unable to comment. 

Quantitative Methods. — In order to separate and determine the mixed 
bases when present in the form of the drug extract and when no other 
alkaloids are present the method described in the Pharmacopoeia should 
be employed. 

When the pure alkaloids alone are present, they may be separated by 
shaking out the alkaline solution with chloroform and the solvent solu- 
tion evaporated and weighed ; due precautions being taken as regards the 
manipulation, and removal of interfering substances, if present, from acid 
solution. 

When the drugs are mixed with other alkaloid-bearing drugs, pure alka- 
loids, or substances of a basic nature, one has to study the individual 
cases to effect a quantitative separation and in some* instances the deter- 
minations will be difficult if not impossible from an exact standpoint. 
The fact that the tropeins are held in solution when the platinum salts 
of the other alkaloids are precipitated in dilute acid solution may be used 
as a basis of many operations. 

Determination of Atropin in Tablets of Atropin Sulphate. — Weigh 25 
tablets and introduce directly into a small separator. Moisten with 5 
mils water. Add 1 mil stronger ammonia water. Agitate with 25 mils 
chloroform and allow to stand until separation is complete. Draw off 
the chloroform into a second separator and repeat the agitation twice more 
with 25-mil portions of the solvent. After combining all of the fractions, 
wash the combined chloroformic solutions by agitation with 10 mils of 
distilled water and allow to stand fifteen minutes. Introduce a pledget 
of absorbent cotton into the stem of the separator and run off the chloro- 



ALKALOIDS DERIVED FROM PYRROLIDIN 115 

form into a tared dish, but do not allow the wash water to enter the orifice 
of the stop-cock. Add 10 mils chloroform and when the water has entirely 
risen to the surface, run off the chloroform into the tared beaker. Wash 
off the outer surface of the stem of the separator with a little chloroform 
and then evaporate over a steam or water-bath, using a fan or blower and 
removing from the bath as the last portions evaporate to avoid decrepi- 
tation. Dry to a constant weight in a vacuum desiccator and weigh as 
atropin. The weight of the atropin may be checked by dissolving the 
residue in neutral alcohol, adding an excess of N/10 sulphuric acid and 
titrating back with N/50 potassium hydroxide. 
Calculate to atropin sulphate 

1 mil N/50 H 2 S0 4 = . 005741 gram atropin 

Factor for atropin to atropin sulphate 1.1695. 

BELLADONNA PLASTER 
U. S. P. Method 

Introduce 10 grams of Belladonna plaster into a 100-mil flask. (If 
the plaster is spread on fabric, cut the portion to be assayed into strips, 
weigh it accurately, and introduce into the flask.) Now add 50 mils of 
chloroform, and shake the mixture until the plaster is dissolved. Pour 
the chloroform solution into a 250-mil beaker and wash the cloth upon 
which the plaster was spread with two portions of 25 mils each of chloro- 
form, adding the washings to the chloroform solution in the beaker. Then 
wash this cloth with 80 mils of alcohol containing 1 mil of ammonia water 
and pour the washings into the chloroform solution in the beaker. Stir 
the mixture gently and allow it to stand until the rubber has separated 
into a compact mass. Dry the cloth upon which the plaster was spread, 
weight it, and subtract its weight from the original weight of the plaster. 
Pour the chloroform-alcohol solution into a 350-mil separator, rinse the 
beaker and rubber with 10 mils of alcohol and add the rinsing to the sepa- 
rator. Then add to the separator 100 mils of distilled water, rotate until 
thoroughly mixed and allow it to stand until the liquids separate. Then 
draw off the chloroform into a second separator containing 50 mils of dis- 
tilled water, shake it thoroughly and after separation draw off the chloro- 
form into a beaker and pour the aqueous solution into the first separator. 
Return the chloroform solution to the second separator and shake out 
the contents of the first separator with two portions of 10 and 5 mils, 
respectively, of chloroform, adding them to the chloroform in the second 
separator. Completely extract the alkaloids from the chloroform solution 
by shaking it out repeatedly with weak sulphuric acid. Collect the acid 



116 ALKALOID AL DRUGS 

washings in a separator and add ammonia water until the solution is 
decidedly alkaline to litmus, and completely extract the alkaloids by 
shaking out repeatedly with chloroform. Filter the chloroform solution 
through a pledget of cotton, evaporate it to dryness, and dissolve the alka- 
loids from the residue in exactly 5 mils of N/10 sulphuric acid V. S., and 
titrate the excess of acid with N/ 50 potassium hydroxide V. S., using coch- 
ineal T. S. as indicator. 

Each mil N/10 sulphuric acid V. S. consumed corresponds to 28.92 
milligrams of the alkaloids from belladonna leaves. 

Toxicological Testing. — In toxicological work the use of mineral acids 
should be avoided, the residues and organs being extracted with alcohol 
in the presence of acetic or tartaric acid. The alkaloids are best obtained 
by shaking out an ammoniacal solution with chloroform and if impure a 
second solution and extraction made. Atropin is rapidly absorbed by 
all parts of the bod}^ and distributed in the blood. 0.03 gram atropin 
after standing twelve years in contact with decomposing blood, beer, and 
other organic substances can still be detected. In case of suspected atro- 
pin poisoning the urine should be carefully examined. 

After taking into consideration the pharmacological action if it is pos- 
sible to ascertain it, one should apply Vitali's test to a portion of the residue, 
assure himself of the absence of strychnin with another, perform a physi- 
ological test on the eye of a cat with another, and obtain a sufficient 
quantity of the cr} T stalline gold salt and picrate to test under the micro- 
scope and obtain melting-points. 

To prepare a solution for pharmacological testing proceed as follows: 
Dissolve the residue in a small quantity of dilute acetic acid and evapo- 
rate cautiously over the steam-bath. Add solid sodium bicarbonate in 
small quantity until no longer acid, then filter into a clean tube or small 
flask and preserve carefully corked until ready to apply. 

ALKALOIDS OF THE POMEGRANATE TREE 

Pelletierin, C 8 Hi 5 NO. 
Isopelletierin, CsHnNO. 
Methylpelletierin, C 9 H 15 NO. 
Pseudopelletierin, C9H15NO. 

These four alkaloids and probably others occur in the bark of the pome- 
granate, Punica granatum (Punicacea?) . The barks of the root and stem 
comprise the drug, and the alkaloidal content ranges from 0.2-4 per cent. 
The bark is also rich in tannin. It is stated that the drug is sometimes 
adulterated with the root barks of the box (Buxus) and barberry. 

Neither pomegranate nor its alkaloids have a very extended use, so 
the drug analyst will seldom have occasion to identify or determine them. 



ALKALOIDS DERIVED FROM PYRROLIDIN 117 

The drug has been successfully employed for the expulsion of tapeworm 
and hence should be sought for in anthelmintics. 

Pelletierin and isopelletierin may be separated from methylpelletierin 
and pseudopelletierin by treating an acid solution of the mixed bases with 
sodium bicarbonate, which liberates the two latter. They may then be 
removed by a suitable solvent, and the former subsequently liberated by 
strong alkali. Commercial pelletierin sulphate and tannate are mixtures 
of all of the pomegranate alkaloids. Pseudopelletierin is the only one of 
the group that has been carefully studied constitutionally. 

Pelletierin 

Pelletierin, also known as punicin, is a colorless oily liquid when freshly 
prepared, but becomes dark and resinous on exposure to air. It has spe- 
cific gravity 0.988 at 0°, is dextrorotatory, becoming inactive when heated 
to 100°, and its salts are laevorotatory. It boils at 195° with some decom- 
position. It is somewhat soluble in water and dissolves readily in alcohol, 
ether, and chloroform, and slightly in petroleum ether. It gives pre- 
cipitates with all of the ordinary alkaloidal reagents except platinic chlor- 
ide. It gives no characteristic color tests with strong acids or oxidizing 
agents. The residue obtained on evaporating a solution of pelletierin in 
strong nitric acid gives a strong mousy odor on treatment with alcoholic 
potash. 

Isopelletierin is probably a stereoisomer of pelletierin; it resembles 
this base in all its properties except that it is inactive. 

Methylpelletierin 

This is a liquid boiling at 215°, somewhat soluble in water and readily 
soluble in alcohol- ether and chloroform. Its hydrochloride is dextro- 
rotatory. 

Pseudopelletierin 
H2 H H2 

c — c c 

1 I V \ 

H 2 C N— CH 3 C=0 

I ! / 

c — c c 

H2 H H2 

Pseudopelletierin or n-methylgranatolin stands in close relationship 
chemically to the tropa alkaloids. Its oxygen atom is ketonic and it yields 
an oxime with hydroxlamine. With sodium and alcohol the C=0 group 
is converted into CHOH and methylgranatolin results, melting at 100°. 
The latter base on treatment with alkaline permanganate loses the CH3 
group and becomes granatolin, melting 134°. 



118 ALKALOIDAL DRUGS 

The alkaloid forms prismatic crystals, melting at 48°, inactive, readily 
soluble in water, alcohol, ether, chloroform, and slightly in petroleum ether. 
It is claimed that this alkaloid is not an anthelmintic. 

THE COCA ALKALOIDS AND SYNTHETIC ANESTHETICS 

The leaves of Erythroxylon coca and E. truxillense (Erythroxylaceae) 
contain the following alkaloids: 

Cocain, C17H21NO4. 
Cinnamyl cocain, C19H23NO4. 
Alpha Truxillin, (Ci 9 H 23 N04)2. 
Beta Truxillin, (CigEfeNO^. 
Benzoyl Ecgonin, C16H19NO4. 
Tropacocain, C15H19NO2. 
Hygrin, C 8 H 15 NO. 
Cuscohygrin, C13H24NO2. 

Coca grows in Peru and Bolivia in large quantities and less in Ecuador, 
Colombia, Brazil, and Argentine. It is also cultivated in the West Indies, 
Ceylon, Java, Zanzibar, and Australia. 

There are two classes of Coca leaves used commercially, the wide and 
the narrow. The former includes the Bolivia, Huanoco, Munzon, and 
Cusco varieties and the latter the Truxillo. The wide leaf is the richest 
in cocain, containing 0.3 per cent 0.8 per cent total alkaloids, 70 per cent 
to 90 per cent of which is cocain. The narrow leaves run from 0.3 per 
cent to 0.9 per cent total alkaloids, about 30 per cent to 50 per cent of 
which is cocain. 

Large quantities of crude cocain are shipped into commerce from 
South America, the material being refined by manufacturers in this country 
and elsewhere. 

An extract of the drug is used in some medicines designed for gastric 
and intestinal indigestion, malassimilation of food, in cachexias, as a stimu- 
lant and general tonic in cases of fatigue and weakness, and to combat the 
effects of opium and alcohol. 

The chief ingredient, cocain, is a local anesthetic and has a wide use. 
It is employed in surgery, ophthalmic practice, and dentistry, and it was 
formerly sold to the public in large quantity in the form of asthma cures, 
hay fever remedies, catarrh snuffs, and dope cures. 

Extract of Coca is often found combined with extracts of celery and 
kola in form of elixirs, to which other extracts are sometimes added, as 
Viburnum. In wines it occurs combined with beef extract and with iron. 
It is also found in combination with malt extract. Prior to the passage 
of the Food and Drugs Act, Coca extract, with its full content of alkaloids, 



ALKALOIDS DERIVED FROM PYRROLIDIN 119 

was used as an ingredient of popular soft drinks, where it functionated in 
combination with Kola extract and caffein. The practice ceased several 
years ago. 

Solid extract of coca is an ingredient of some aphrodisiac pills, being 
mixed with phosphorus, Nux Vomica, and often cinchonidin; and in 
sedative compounds with valerian, Cannabis sativa, arsenic, strychnin, 
and occasionally codein. 

Cocain in the form of its salts occurs in tablet triturates, dental and 
ophthalmic tablets, often combined with morphin and atropin, and in 
various compressed tablets, one of the most important being a throat tablet 
where it is present with menthol, benzoic acid, eucalyptol, and oil of anise. 
Again it is combined with borax and potassium chlorate in voice tablets. 

Cocain — (Methyl — benzoyl — ecgonin) 

CH 2 CH CHCOOCH3 

I \ 

N— CH3 CHOOCCoHs 

I / 

CH2 CH CH2 

Cocain occurs in all Coca leaves. It crystallizes from alcohol in 4- to 
6-sided prisms melting at 98° C. It has a slightly bitter taste and numbs 
the nerves of the tongue. When the tongue or lips have been rubbed with 
the alkaloid they gradually become numb and feel smooth like ivory until 
the effect wears away. 

It is soluble in 700 parts water at 12° C, 10 parts alcohol, and 4 parts 
ether, and is also soluble in benzol, toluol, carbon bisulphide, carbon 
tetrachloride, chloroform, petroleum ether, acetic ether, amyl acetate, ace- 
tone, kerosene, aniline, turpentine, olive oil. It is insoluble in glycerin. 

It turns the plane or polarized light to the left [a]d — 71° 95'. 

It is a monoacid base and is readily soluble in dilute acids. It is alka- 
line to litmus and methyl orange, but does not affect phenolphthalein. Its 
aqueous solutions are precipitated by ammonia, alkalies and alkali car- 
bonates. 

It is precipitated by potassium ferrocyanide, all of the general alka- 
loidal reagents, Mayer's, Wagner's, tannic acid, phosphomolybdic acid, 
platinum chloride, gold chloride, by chromic acid on acidulation, by zinc 
sulphocyanide, by palladium chloride in presence of chlorine water, by 
mercuric acetate, the precipitate being soluble in excess on standing, but 
is not precipitated by potassium ferricyanide. It forms with bismuth a 
double iodide and gives an oily precipitate with potassium bichromate. 

Boiling water hydrolyzes cocain to benzoyl-ecgonin and methyl alcohol, 
while by alkalies it goes to ecgonin and benzoic acid. It is completely 



120 ALKALOIDAL DRUGS 

hydrolyzed to ecgonin, benzoic acid, and methyl alcohol by heating for 
several hours in a pressure flask over the steam-bath. 

Cocain gives no characteristic color reactions on which any reliance 
can be placed when working with small quantities. 

The physiological test is characteristic, though of course other sub- 
stances produce anesthesia, and this alone will not identify cocain. 

When moistened with nitric acid and evaporated to dryness, the resi- 
due on addition of a few drops of alcoholic potash will give the odor of 
ethyl benzoate. This odor cannot be mistaken, but it disappears quickly 
if the amount of the alkaloid is small and hence caution must be used in 
applying the test. If the odor of the alcohol is confusing, a little water 
should be added and the contents heated. This is one of the best tests 
for cocain, quantities as small as .2 mg. being readily detected. The pro- 
cedure is that of Vitali for the detection of atropin, which gives a beautiful 
violet color. Tropacocain will also give the ethyl benzoate odor. Hyos- 
cyamin, strychnin, codein, and physostigmin give color reactions and the 
latter develops an odor resembling phenyl-isocyanide. Delphinin, brucin, 
and veratrin develop slight odors which, however, cannot be mistaken for 
ethyl benzoate. Until perfectly familiar with this odor a parallel test 
should be made using a sample of cocain. 

On heating cocain with dilute hydrochloric acid under pressure for 
four hours over steam, the odor of methyl benzoate can be detected on 
opening the flask. Tropacocain gives no such odor. 

On heating cocain with dilute hydrochloric acid containing a few crys- 
tals of salicylic acid, under pressure over the steam-bath, a marked winter- 
green odor will be apparent on opening the tube. This test will distinguish 
cocain from tropacocain. 

If 2 to 3 mils of chlorine water are added to a cocain solution and then 
several drops of 5 per cent palladium chloride solution are added, a red 
precipitate is formed which is insoluble in alcohol and ether, but soluble 
in sodium thiosulphate. 

On adding 5 drops of a 5 per cent chromic acid solution to a cocain 
solution, a yellow precipitate will be formed which disappears on shaking. 
On the addition of 1 mil of concentrated hydrochloric acid a permanent 
yellow precipitate is formed. If truxillin is present reduction of the chro- 
mic acid takes place. Ecgonin, spartein, atropin, caffein, pilocarpin, 
codein, and morphin do not form yellow precipitates with chromic acid 
or potassium chromate. Quinin, quinidin, cinchonin, cinchonidin, hydro- 
quinin, apomorphin, brucin, strychnin and veratrin form precipitates with 
5 per cent chromic acid if the solutions are neutral, but cocain only gives 
the precipitate after the addition of hydrochloric acid. 

A solution containing not less than 1 per cent cocain gives a copious 
red precipitate on the addition of potassium permanganate. The behavior 




ALKALOIDS DERIVED FROM PYRROLIDIN 121 

with permanganate serves also to detect an admixture of cinnamyl-cocain 
and certain other impurities. The presence of these causes an immediate 
reduction in the cold, the first drop or two of the reagent produces a brown 
coloration, while the precipitate produced by a further addition is more 
or less brown instead of a violet red. 

Cocain is removed from an ammoniacal solution by all of the immis- 
cible solvents. In the case of caustic alkalies where the mixture has been 
heated and subsequently cooled, the cocain will not come out to any extent. 
However, attempts to make use of this property as a means of separating 
quinin from cocain have so far led to unsatisfactory results. 

Cocain is easily broken down by evaporating it in acid or alkaline 
solution or even boiling it with water. 

Cocain Hydrochloride 

Cocain hydrochloride is the principal commercial salt of this alkaloid. 
It occurs in the form of prismatic crystals or lustrous leaflets and is readily 
soluble in water and alcohol. If 5 mils of a 1-50 solution in water are 
treated with 85 mils of water and .2 mil ammonia water (10 per cent), and 
vigorously stirred with a glass rod, a crystalline precipitate will form within 
a short time and the supernatant liquid will be clear. This is the cus- 
tomary reaction taking place when the salt is pure and is known as Mac- 
Lagan's test. The presence of 0.5 per cent of allied coca bases will pre- 
vent the formation of a crystalline precipitate and the liquid will retain 
a milky appearance 

Cinnamyl Cocain 

CH 2 CH CHCOOCH3 

I \ 

NCH3 CHOOCCH=CHC 6 H 5 

I / 

C H2 C H C H2 

Methyl-cinnamylecgonin 

This alkaloid is found in all varieties of coca, particularly in that from 
Java, of which it constitutes one-half the total alkaloids. 

It melts at 121° C, is readily soluble in alcohol, benzol, and ether, 
and sparingly soluble in petroleum ether, but is almost insoluble in water. 
Its solutions are lsevorotatory. It instantly reduces solutions of potas- 
sium permanganate and the odor of benzaldehyde is given off on 
warming. 

On heating over the steam-bath under pressure in presence of acid it 
is easily decomposed into cinnamic acid, ecgonin, and methyl alcohol. 

It does not give the ethyl benzoate test which is so characteristic of 
cocain, the ester formed in this case having the odor of ethyl cinnamate. 



122 



ALKALOIDAL DRUGS 



Furthermore, on evaporating with nitric acid the odor of benzaldehyde 
is apparent. 

Cocain may be readily separated from cinnamyl cocain on account of 
the ease with which the latter is oxidized by permanganate, in fact experi- 
ments conducted by Garsed show that the cocain can be recovered quanti- 
tatively. 



CH 2 — CH- 

I 



Alpha and Beta Truxillins 

C 6 H 5 CH3COOCH — CH 

I / I 

CHCOOCH3 CH— CH— COOHC NCH 3 

\ II \ I 

NCH 3 CHOOC CH— C 6 H 5 CH 2 — CH — 

I / 

CH2 — CH CH2 

CH 2 — CH CHCOOCH3 



NCH 3 CHOOC— CH— CH— C 6 H 5 

I / II 

-CH 2 



-CHc 



CH 2 



CH 2 — CH CH 2 CH — CH — C6H5 

CH 2 — CH -CHCOOCH3 

I \ 

NCH3 CHOOC — 

I / 

CH 2 — CH CH 2 

Alpha truxillin, cocamin, isatropyl-cocain, as it is variously called, 
is amorphous. It melts at 80° C, is little soluble in water and petroleum 
ether, but soluble in the other organic solvents. Its solutions are laevo- 
rotatory. It is quite bitter. 

Beta truxillin possesses similar properties, it is amorphous and begins 
to melt at 45° C. It differs from the alpha by its slight solubility in alcohol. 

The acid products of hydrolysis, cocaic, isatropic, or truxillic acids are 
polymers of cinnamic acid and on distillation are converted into this acid. 
They do not absorb halogens and on oxidation do not yield benzaldehyde, 
hence they have no double bond. They are much more insoluble in water 
than either benzoic or cinnamic acids and may be separated from them 
by simply filtering an aqueous solution which is sufficiently dilute to hold 
up the benzoic and cinnamic acids. 

The truxillins are not oxidized by permanganate and may be separated 
from cinnamyl-cocain in a manner similar to cocain. 

In order to identify the cocain in a mixture of the same with cinnamyl 
cocain and the truxillins, the solution should be treated with perman- 
ganate. The benzoic acid formed in this reaction may be removed by 
shaking out from acid solution with ether and then the residual solution 



ALKALOIDS DERIVED FROM PYRROLIDIN 123 

heated for three or four hours in a pressure flask over the steam-bath. 
By evaporating to a dilution of about 1-400 the benzoic acid will remain 
dissolved when cooled to 12° C, while the truxillic acid will be almost 
completely separated. The solution may be filtered and the clear filtrate 
shaken out with ether, which will remove the benzoic acid formed by the 
hydrolysis of the cocain. It can then be identified by its melting-point 
and other characteristic tests. 

Benzoyl Ecgonin 

CH 2 — CH CHCOOH 

I \ 

NCH3 CHOOCC 6 H 5 

I / 

CH2 — CH CH2 

This substance exists naturally to some extent and results from the 
partial saponification of cocain. It is soluble in water and alcohol but 
only slightly soluble in ether. The hydrous form melts at 90° C. and 
the anhydrous at 195° C. It is soluble in alkalies. 

Tropacocain. Benzoyl Pseudotropin 

CH 2 — CH CH 2 

I \ 

NCH3 CHOOCCeHs 

I / 

CH 2 — CH CH 2 

This alkaloid crystallizes from ether in plates having a melting-point 
of 49° C. It is insoluble in water, but dissolves in alcohol and follows 
cocain very closely in solubility in the organic liquids. 

On hydrolysis with dilute mineral acids it splits up into benzoic acid 
and pseudotropin. It gives precipitates with the general reagents for 
alkaloids. 

With potassium bichromate it yields a crystalline precipitate instead 
of the oily residue given by cocain. 

A few drops of a 5 per cent solution of chromic acid precipitates at 
once a solution of a tropacocain salt. When a mixture of the salts of 
both cocain and tropacocain are treated with 5 per cent chromic acid the 
tropacocain is precipitated at once and agglomerates, sticking to the side 
of the tube. On filtering and adding hydrochloric acid to the filtrate, a 
copious precipitate characteristic of the cocain compound is formed. 

It gives a precipitate with mercuric acetate which does not go into 
solution again on standing as in the case of cocain. 

With potassium ferricyanide it gives a precipitate of needle-like crys- 
tals gradually appearing. Cocain does not precipitate with this reagent. 

Hesse states that on account of its solubility in dilute ammonia it may 
be separated from the other coca alkaloids. 



124 ALKALOIDAL DRUGS 

Hygrin 

This is a liquid having a boiling-point of 193-195° C. It is a tertiary 
base, contains a N methyl group but no methoxyl. Its oxygen is ketonic 
in character, since it forms an oxime which can be distilled almost un- 
changed. It is easily soluble in alcohol, but wLh difficulty in water, ether, 
and petroleum ether. It is decomposed by light. 

On oxidation with chromic acid, monbasic hygric acid, C5H10NCOOH, 
results, which crystallizes with one molecule of water and melts at 164°. 

It absorbs carbon dioxide from the air and also forms a hydrochloride 
and a hydroiodide. It gives a well-defined needle-like picrate melting at 
148°. (160° Beilstein.) 

Lieberman claims that hygrin occurs chiefly in the Cusco leaves, where 
it is present to about 0.2 per cent. 

As obtained from coca leaves hygrin is not a substance of definite com- 
position, but consists of a mixture of liquid bases which can be separated 
from each other only with difficulty. 

To prepare hygrin, according to Lieberman and Cybulski, 200 grams 
of impure hygrin obtained from Cusco leaves were strongly acidulated 
with 150 mils 33 per cent hydrochloric acid to decompose the acylecgonin 
present and boiled for one hour on the water-bath with an air cooler, the 
acids were separated with ether and then 250 grams concentrated potas- 
sium hydroxide (2-1) added, and the bases dissolved out with ether. The 
ether solution was washed with caustic alkali or with barium hydroxide, 
the ether then distilled and the residual oily bases fractionated. Hygrin 
goes over between 92-94° at 20 mm. pressure, or at 111-113° at 50 mm., 
specific rotation [a] D — 1.3°. The high boiling constituent of the basic mix- 
ture consists, according to the authors, of cuscohygrin and /3-hygrin. 

The presence of hygrin and cuscohygrin in extracts of dried coca leaves 
is a matter of controversy at the present stage of our knowledge of this 
class of alkaloids. That they occur in the fresh leaves has been definitely 
ascertained, and from work done on the extracts of dried leaves it is prob- 
able that they exist there also, but further experimental research into the 
phytochemistry of the drug is needed before the obscure points can be 
definitely settled. 

Dr. Rusby after an extended research on the subject of the coca leaf 
was satisfied that, before exportation, the drug contained a much higher 
percentage of alkaloid. It is his belief that during transit the leaves lose 
some volatile substance, perhaps hygrin.- 

Cuscohygrin 

This is also a liquid of oily nature and boils at 185° C. at 32 mm. It 
is easily soluble in water, forms a hydrate which melts at 40-41° C, and 
a well-defined nitrate which permits its separation from hygrin. 



ALKALOIDS DERIVED FROM PYRROLIDIN 125 

It is a di-acid tertiary base with a methyl group attached to each 
nitrogen. 

PRODUCTS OF HYDROLYSIS OF THE PRINCIPAL COCA ALKALOIDS 

On heating the alkaloids to 80-100° C. with hydrochloric acid prefer- 
ably under pressure, or boiling with alcoholic potash they act as follows: 

Cocain, C17H21NO4+H2O = C16H19NO4+CH3OH 

Benzoyl ecgonin 

then C16H19NO4+H2O = CgHisNOs+CeHsCOOH 

Ecgonin ' 

Cmnamyl Cocain, C19H23NO4+H2O = C18H21NO4+CH3OH 

Cinnamyl Ecgonin 

then C18H21NO4+H2O = C9H15NO3+C9H8O2 

Ecgonin Cinnamic Acid 

Truxillin, C38H46N 2 Og+3H 2 = C9H15NO3+C27H29NO6+2CH3OH 
then C27H 2 9N0 6 +H 2 = C9H15NO3 + C18H16O4 

Ecgonyl cocaic acid Truxillic acid 

Tropacocain, C17H19NO2+H0O = CsHisNO+CeKsCOOH 

Pseudotropin 

The ease with which the Coca alkaloids are decomposed is taken ad- 
vantage of in the commercial field. The mixed alkaloids are hydrolyzed, 
the resulting acids separated and then the ecgonin converted to cocain. 

Ecgonin is a solid substance containing one molecule of water melting 
at 198-199° C. It is readily soluble in water and its solutions are laevo- 
rotatory. It is soluble in ethyl acetate, slightly soluble in alcohol, almost 
insoluble in ether, and does not dissolve in acetone, chloroform, toluol, 
carbon bisulphide or carbon tetrachloride. / 

It acts as a tertiary base, a monatomic alcohol, and a monacid base. 
It forms quaternary salts, esters, and normal salts with alkalies which 
are not decomposed by carbon dioxide. Ecgonin solutions are neutral 
to litmus, a fact which caused Einhorn to suggest that the acid and basic 
elements in the molecule neutralized each other, yielding a betaine-like 
structure. At a dilution of 1-500 it is not precipitated by N/100 iodine, 
but stronger solutions yield precipitates with iodine. 

Ecgonin is not precipitated by potassium mercuric iodide, but forms 
a very insoluble compound with phosphotungstic acid. It is not removed 
from aqueous solutions by immiscible solvents except possibly to a slight 
degree by ethyl acetate. 

The identity of ecgonin is best established by converting it to cocain 
and isolating and identifying the alkaloid. The material under exami- 
nation should be brought into solution, made slightly alkaline with caustic 
alkali and the alkaloids removed by agitation with Prolius mixture. The 



126 ALKALOIDAL DRUGS 

extraction must be continued as long as any substance is removed which will 
give a precipitate with Mayer's reagent. If the solution is a plant extract 
or contains any quantity of foreign matter, it is then neutralized with acetic 
acid and treated with an excess of Howe's basic lead acetate. After filter- 
ing, the excess of lead is removed by potassium oxalate, the filtrate evap- 
orated and the residue thoroughly extracted with pure anyhdrous methyl 
alcohol. The alcohol solution is warmed, subjected to the action of dry 
hydrochloric acid gas for about ten minutes, heated again and the treat- 
ment with hydrochloric acid repeated, this procedure being continued, 
adding more methyl alcohol if necessary, for about one-half hour. The 
mixture is then transferred to a larger and long thick test-tube, the alcohol 
evaporated, benzoyl chloride added, and the tube heated in an oil-bath 
at 180-200° C. for one-half hour. At the end of this time the tube is 
cooled and the contents washed out with ether and sodium bicarbonate 
solution. After agitation with three portions of ether, the combined 
solvent solutions are shaken out with dilute sulphuric acid, the acid sepa- 
rated, made alkaline with sodium bicarbonate and agitated with low- 
boiling petroleum ether, which will dissolve any cocain which may have 
been formed, and on evaporating the solvent the residue can be subjected 
to the identity tests for that alkaloid. 

On boiling with baryta Water methylamine is formed. 

On treatment with phosphorus pentachloride a molecule of water is 
lost and anhydroecgonin is formed, which is soluble in water and alcohol 
but almost insoluble in ether. 

On heating with hydrochloric acid, carbon dioxide is given off and 
tropidin formed. 

Several stereoisomers of ecgonin have been prepared synthetically. 
^ Pseudotropin forms crystals melting at 106° C, boiling 241-243° C. 
\ Soluble in water, chloroform, alcohol, but sparingly soluble in ether. 

By heating with glacial acetic acid and sulphuric acid tropidin results. 

The truxillic acids have already been discussed to some extent under 
the truxillins. They are not volatile with steam, as are both benzoic and 
cinnamic acids, and are much more insoluble in water, dilutions of 1-40,000 
giving a distinct precipitate. Truxillic acid melts at 274°. Iso-truxillic 
acid melts at 206°. 

The acid is nearly insoluble in ether, from which it crystallizes in a 
form resembling benzoic acid. 

The barium salt of alpha-truxillic acid is soluble in water, while that 
of the beta acid is insoluble. 

The alpha acid is obtained in about double the amount of the beta. 

The alpha acid on treatment with acetic anhydride and subsequently 
with a base is converted into an isomeric acid called gamma-truxillic acid. 

The beta acid on fusion with alkali is converted to delta-truxillic acid. 



ALKALOIDS DERIVED FROM PYRROLIDIN 127 

IDENTIFICATION OF THE COCA ALKALOIDS 

The analyst of galenical preparations will be called upon to detect the 
presence of cocain in liquid preparations containing extract of coca leaf 
and in preparations where it is used as a salt of the pure alkaloid, also to 
differentiate between it and other alkaloids and various anesthetics of 
synthetic origin. 

As cocain is the chief active ingredient of coca leaf, except possibly 
that of East Indian origin, little difficulty need be experienced in substan- 
tiating its presence in products containing the extract. If by chance one 
is working with a product where the amount of cinnamyl cocain predomi- 
nates, the fact that this latter alkaloid is in large quantities may be readily 
ascertained from a knowledge of its properties taken into consideration 
with those of cocain, and if the cinnamyl cocain is found it may be removed 
by making use of the permanganate reaction. 

As obtained from a drug extract the alkaloidal residue is seldom crystal- 
line, but has the consistency of a thick oil. If the final extraction has been 
made with low-boiling petroleum ether, the residue will often crystallize 
on standing overnight. The deposit is usually without color, but it has a 
characteristic odor. It has no color reactions on which any reliance can 
be placed, but its character may be readily determined by placing a bit 
on the end of the tongue and rubbing it gently for about a minute. A sen- 
sation of numbness develops gradually, the tongue and often the lips 
which have been touched by the finger will have a smooth, ivory-like 
feeling, and the effect will be apparent for some time. 

The residue will give the ethyl benzoate test, and by proceeding accord- 
ing to the method of Garsed described on a subsequent page for determin- 
ing the alkaloids, a separation and identification of the cocain, cinnamyl 
cocain, and the truxillins may be accomplished. Ecgonin and benzoyl 
ecgonin are so soluble in aqueous liquids that they are not removed by 
ether. 

Aconitin will also give the ethyl benzoate test, but it is seldom if ever 
found with coca alkaloids, and the physiological test would establish its 
presence at once. 

From a solution or other preparation where cocain is present in the 
form of a pure salt, the alkaloid will be obtained, when not mixed with 
other alkaloids, in a form which is usually crystalline and which gives a 
sharp melting-point. In all cases the alkaloid should first be brought into a 
solution slightly acid and free from alcohol. The solution should first be 
shaken out with ether and chloroform, then made ammoniacal and shaken 
out with low-boiling petroleum ether. The petroleum-ether solution 
should be separated, filtered into a small beaker or dish, and evaporated 
over the steam-bath. The residue, if pure cocain, will give its character- 
istic reactions, 



128 ALKALOIDAL DRUGS 

Tropacocain in the form of its pure salt is used medicinally, though 
not to any great extent. It may be readily distinguished from cocain 
by its melting-point, by not giving the methyl salicylate test, by its immedi- 
ate precipitation by 5 per cent chromic acid from neutral solution, by its 
precipitation with potassium ferricyanide, and by the permanence of the 
precipitate formed with mercuric acetate. 

Other common alkaloids which might be removed simultaneously from 
an ammoniacal solution by means of petroleum ether, may be distinguished 
from cocain as follows: 

Coniin and nicotin may be eliminated, as they would almost never 
occur. However, the white fumes which develop by bringing a drop of 
hydrochloric acid on a glass rod near the surface of a residue containing 
them would be an indication of their presence. They are both volatile 
and would not interfere with the ethyl benzoate test. 

Atropin, which often occurs with cocain, would be detected by Vitalis 
color reaction, at the same time the ethyl benzoate test is performed. 

Quinin would be apparent by the intensely bitter taste of the residue, 
and the presence of cocain will not interfere with the thalleoquin reaction. 
The physiological test will show the presence of cocain. 

Caff ein does not interfere with the ethyl benzoate test, and the pres- 
ence of cocain does not harm the Murexide test for cafTein. Moreover, 
caffein would be removed by previously shaking out the acidulated solu- 
tion with chloroform, and again it is practically insoluble in petroleum 
ether. 

Morphin, while it is often used with cocain, would not appear in the 
petroleum ether shake-out. 

The distinguishing tests between cocain and the synthetic anesthetics 
will be described after a consideration of the properties of these substances. 

SEPARATION AND IDENTIFICATION OF SMALL QUANTITIES OF COCAIN 

If the substance under examination is a solid it should be dissolved in 
water, if possible, or in normal sulphuric acid: if it contains much drug 
material and is not readily dissolved in water an extraction with alcohol 
should be resorted to, water added to the mixture, and the bulk of the 
alcohol subsequently evaporated. Liquid products, such as sirups, need 
no prelimimary treatment unless they are very thick or in the form of 
emulsion; in the former case they should be diluted to about the consist- 
ency of a 50 per cent sugar solution, and in the latter some method which 
will separate the gum and fatty material must be adopted. 

Having obtained a clear solution of the substance in question the pro- 
cedure is as follows: 

Transfer the solution to a separator and add a slight excess of ammo- 
nium hydroxide. (If the product was originally alkaline it is best to acidify 



ALKALOIDS DERIVED FROM PYRROLIDIN 129 

it and then add a slight excess of ammonia. If a precipitate is formed 
it should be separated by filtration and the filtrate used for analysis.) 
Shake out the solution with 50 mils of Prolius mixture (ether 4 parts, 
chloroform 1 part, and alcohol 1 part), and allow to stand; then Collect 
the clear solvent in another separator and shake out the aqueous solu- 
tion twice more with the Prolius mixture. Filter the combined solvent 
solutions through a creased paper into a beaker and evaporate the liquid 
over a steam-bath, using a fan. Do not allow the residue to dry, but as 
soon as the last portions of alcohol are driven off remove the beaker from 
the steam. Add 25 mils of normal sulphuric acid in 10-mil portions, warm 
the mixture slightly and then filter into a separator after each portion of 
the dilute acid is added, and finally wash with a little water. Then shake 
out the solution five times with 15-mil portions of chloroform, preserving 
the chloroformic extracts in another separator. Wash the latter with 10 
mils of distilled water, discard the chloroform, and add the wash water 
to the acid liquid which was shaken out with the chloroform. Then add 
10 mils of petroleum ether (boiling at 40°-60° C.) and thoroughly shake 
the separator, separate the acid liquid, and discard the solvent. Add a 
slight excess of ammonium hydroxide, cool the mixture, and then shake 
out the solution with 15 mils of petroleum ether of the boiling-point before 
specified and reserve the solvent solut on in another separator. Shake 
twice again with the same quantity of solvent, ^hen wash the combined 
petroleum ether solutions once with distilled water and filter into a small 
beaker, washing the separator and filter with 10 mils of petroleum ether. 
Evaporate the petroleum ether rapidly over a steam-bath, using a fan, 
and if cocain was present in the original material it will be found in the 
residue. 

By this method it is possible to obtain the cocain in a very pure con- 
dition; in fact, it will often crystallize in a few hours, even though the 
amount present be very small. The identification tests are conducted as 
follows : 

Dissolve the residue in petroleum ether and pour p )rtions of the sol- 
vent into a beaker and a small evaporating dish, reserving the remainder 
for subsequent tests. After the solvent has evaporated dissolve the con- 
tents of the beaker in 5 mils of normal sulphuric acid, warming if necessary, 
and add potassium mercuric iodide test solution. 

The formation of a precipitate indicates the presence of an alkaloid, 
but, of course, does not identify it as cocain; if no precipitate occurs 
further tests are unnecessary. 

To identify the alkaloid treat the contents of the evaporating dish 
with 2 mils of concentrated nitric acid and evaporate the mixture to dry- 
ness over the steam-bath. When there is no further odor of nitric acid 
remove the dish, cool, and add 5 to 10 drops of N/5 alcoholic potash 



130 ALKALOIDAL DRUGS 

solution, noting carefully the color and odor of the mixture while the dish 
is cool and then applying gentle heat and noting the odor again. 

Minute traces of cocain will give off the odor of ethyl benzoate on 
treatment with nitric acid and alcoholic potash. The odor is very marked 
in its character and can be readily distinguished, though until one is 
familiar with it a parallel test should always be run, using pure cocain. 

The color reaction is also of interest and will prove valuable in detect- 
ing the presence of other alkaloids. A purple color would indicate that 
atropin, strychnin, or yohimbin were present, though it is well known 
that a residue obtained by the above method from the coca leaf will in 
some instances also give a purple color. Tropacocain, benzoylecgonin, 
and aconitin will also give the ethyl benzoate test, but the possibility 
of the presence of the first two can be eliminated by a subsequent micro- 
scopic test, and from the fact that the benzoylecgonin is not removed 
from the aqueous solution to any great extent by petroleum ether. The 
latter fact is also true of aconitin, but the presence of this very poisonous 
alkaloid would be readily apparent when performing the physiological 
test. 

The portions of the material which had been reserved should be tested 
physiologically. The petroleum ether is evaporated, a part of the cool 
residue is placed on the tongue and rubbed gently with the finger for about 
one minute, when, if cocain is present, a sensation of numbness gradually 
develops, the tongue and often the lips which have been touched by the 
finger will have a smooth, ivory-like feeling, and the effect will be apparent 
for some time. This is another test which should be performed in con- 
junction with one on a known sample, unless the analyst is perfectly 
familiar with the sens tion. 

This residue may also be used "or a microscopic test by removing a 
small portion, placing it on a microscope slide and noting, under the lens, 
the character of the crystals found with a drop or two of gold chloride 
solution. Cocain forms a definite crystalline compound with gold chlo- 
ride, and the product obtained should be compared with that given by 
a solution of the pure alkaloid. 

With a residue obta ned originally as described, these tests will sub- 
stantiate the presence of cocain even though it occur in a minute quantity, 
and the four reactions can be applied to very small residues, although if it 
is desired the first mentioned with potassium-mercuric iodide may be 
omitted. 

Another reaction for cocain which is very characteristic when con- 
sidered in conjunction with the ethyl benzoate test is obtained by trans- 
ferring some of the residue to a pressure flask, adding a few crystals of 
salicylic acid and about 15 mils of dilute hydrochloric acid, and heating 
the flask, stoppered, for about an hour and a half over the steam-bath. 



ALKALOIDS DERIVED FROM PYRROLIDIN 131 

On opening the flask the odor of wintergreen will be very marked if cocain 
was originally present. Tropacocain does not respond to this reaction, 
though it might indicate the presence of cinnamyl cocain and the truxil- 
lins; all of the latter, however, are precluded if the mixture gives the ethyl 
benzoate test. 

Howard and Stephenson 1 describe the results of their researches in 
determining the characteristic microscopic forms of the crystals of a number 
of cocain salts, and the essential points of the work are summarized as 
follows: 

Crystalline deposits have been obtained with each of the following 
eleven reagents, viz., palladous chloride, platinum chloride, gold chloride, 
picric acid, chromic acid and hydrochloric acid, potassium dichromate 
and hydrochloric acid, potassium permanganate, potassium chromate, 
sodium carbonate, ferric chloride, and potassium hydrate or sodium hy- 
drate; noncrystalline deposits were obtained with chlorzinc iodid, picra- 
lonic acid, Mayer's reagent, phosphomolybdic acid, phosphotungstic acid, 
Kraut's reagent, Wagner's reagent, barium mercuric iodide, and potas- 
sium cyanide. 

The following observations were noted concerning the various react- 
ions with cocain in which crystals were produced: 

Palladous Chloride — Tins is one of the most characteristic tests for 
cocain, though not quite so sensitive as gold chloride. The crystals vary 
in form greatly, according to the conditions of precipitation. There is 
at first formed, except in very dilute solutions (1 : 300 and up), an orange- 
colored amorphous-like or oily precipitate from which, on standing, crys- 
talline forms of golden-brown color are produced. One of the most com- 
mon forms is that obtained with a 1 : 100 dilution, when feathery crystals 
are formed which have a strong tendency to twin. With a solution of 
1 : 20 a dense precipitate is thrown down, out of which hexagonal plates 
are at first formed and frequently followed later by sheaf-like clusters of 
fine-pointed acicular crystals. A dilution greater than 1 : 500 gives crys- 
tals only with difficulty, crj^stalhzation being induced by rubbing the slide 
with the glass stirring rod. The limit of the test is 0.2 /* gr. 

Platinum Chloride. — With a 1 : 20 solution a dense white precipitate 
is formed and quickly followed by the production of veiy narrow feathery 
crystals — many times twinned so as to resemble a bird with outspread 
wings. Clusters of more than two are also abundant. If the reagents 
are mixed slowly the crystals are more like those of greater dilution. With 
a 1 : 100 dilution the feather type is much more prominent, the secondary 
branches being well developed into frost-like forms. With 1 : 1000 solu- 
tions either short thick crystals are formed or else plate crystals twinning 

1 U. S. Dept. Agri. Bull. 122, Bureau Chemistry, p. 99. 



132 ALKALOIDAL DRUGS 

in a most characteristic manner are produced. The dilution limit is about 
1 : 4000, and the limit in 1 : 1000 is 0.2 M gr. 

Gold Chloride. — This is the most sensitive reagent for cocain so far 
found. At 1 : 100 feathery frost-like crystals are produced, together with 
some nearly smooth star-like aggregates. At 1 : 1000 the form is much 
the same, but the branches usually bear a rough outline. Diamond plates 
are also produced. At 1 : 4000 a cross-like form predominates, the cross- 
bar being short. A few rosette crystals frequently are present. Crys- 
tals can be obtained in dilution up to 1 : 20,000, and the limit of the test 
for dilutions of about 1 : 300 is 0.033 fi gr. 

Picric Acid. — This is a good reagent for dilutions up to 1 : 800, though 
the crystals produced are not very characteristic for this alkaloid. They 
are produced in spherical rosettes (or sheafs) of fine lemon-yellow acicu- 
lar forms. The reaction takes place quickly, and no difficulty is experi- 
enced in producing them nearly to the hmit of dilution. At 1 : 300 the 
limit is 0.2 /i gr. 

Potassium Permanganate. — With cocain, solutions up to a dilution 
of 1 : 700 give purple-colored square plates, or aggregates of this form. 
Vigorous rubbing of the slide is often necessary to start the crystallization, 
which then proceeds readily. When they begin to crystallize sponta- 
neously, the plates are sometimes deposited in spherical aggregates, The 
limit at 1 : 400 is 2 M gr. 

Chromic Acid and Hydrochloric Acid. — This test is made by adding 
a small drop of 5 per cent chromic acid solution to the test drop. A pre- 
cipitate is formed which on stirring disappears (if too much has not been 
added). A small drop of strong hydrochloric acid is added, and a yellow- 
ish deposit is produced which, after rubbing of the slide, should in a few 
moments be transformed into loose spherical clusters of an acicular crys- 
tal. This test appears to be one of the most uncertain, because of the 
chfficult}^ with which the crystallization is sometimes induced to being in 
dilutions greater than 1 : 60. A concentration of 1 : 1000 has produced 
positive results on standing several minutes. The limit appears to be for 
1 : 100 about 3 M gr. 

Potassium Bichromate and Hydrochloric Acid. — This test gives the 
same form of crystals as the chromic acid and the test is conducted in a 
similar manner. The hmit of dilution is about 1 : 1000 while at 1 : 100 
the limit is 3 y. gr. 

Ferric Chloride. — The crystals are spherical aggregates of rather coarse 
blade-like crystals with chisel-shaped ends. The limit of dilution is about 
1 : 1000 and in a dilution of 1 : 100 the hmit is 3 \i gr. 

Potassium Hydrate, or Sodium Hydrate. — This produces a white amor- 
phous precipitate which changes into crystals on standing or by rubbing 
the slide w T ith a glass rod. The crystals are rod-like, frequently with more 



ALKALOIDS DERIVED FROM PYRROLIDIN 133 

or less chisel-like ends and a V-shaped recess extending backward into the 
crystal. There is a strong tendency to form coarse clusters up to about 
fifteen branches. In open drops tree-like forms are frequent. For each 
of these reagents dilutions up to 1 : 1000 give the reaction and the limit 
at 1 : 100 is 3 m gr. 

Sodium Carbonate. — This gives a precipitate with cocain like that 
produced by potassium hydrate, both in the amorphous and crystalline 
forms. Limit of dilution is 1 : 1000. In 1 : 100 solution the limit is 
3 n gr. 

In order to determine the usefulness of some of the above tests when 
other alkaloids are present the palladous chloride test was made on test 
drops to which had been added solutions of one of the following alkaloids : 
codein sulphate, atropin sulphate, heroin, dionin, acoin powder, cinchonin 
sulphate, hydroxylamin hydrochloride, apomorphin hydrochlorate, narcotin, 
papaverin, brucin, narcein, morphin, thebain, gujasanol, orthoform (new), 
cinchonidin sulphate, quinidin sulphate, beta-eucain, holocain, caffein, 
quinin sulphate, strychnin, and tropacocain. In each case the crystals 
of the cocain compound were obtained and in the case of brucin, gujasanol, 
caffein, strychnin, and tropacocain, with which the palladous chloride 
regularly gives a crystalline precipitate, it was found that when cocain 
was also present the cocain product was given in addition to that for the 
other alkaloid, though occasionally with modified form, 

QUANTITATIVE DETERMINATION OF ALKALOIDS IN COCA EXTRACTS 
AND SEPARATION OF COCAIN 

The alkaloidal residue obtained in the assay of coca leaf or the extract 
made from this drug does not show the actual cocain content. This alka- 
loid may be present to the extent of 40-90 per cent. 

From solutions containing extract of Coca, and where the Belladonna 
or Cinchona alkaloids are not present, the Coca alkaloids may be separated 
in the same way as they are from the extract obtained from the drug in 
the assay methods. 

Caffein may be separated from cocain by taking advantage of the fact 
that the former can be removed by chloroform from solution acidulated 
with sulphuric acid. 

The methods for determining the ether soluble alkaloids in Coca leaf 
have already been detailed. 

In order to determine the actual cocain present in the alkaloidal residue 
obtained in the assay of Coca leaf or preparations containing this drug 
the following method of Garsed l may be used : 

The crude alkaloids, after thoroughly drying over sulphuric acid, are 
weighed. Then dissolve in dilute sulphuric acid and add potassium per- 

1 Pharm. J., 1903, 784. 



134 ALKALOIDAL DRUGS 

manganate solution. Re-extract the unoxidized alkaloid from ammonia- 
cal solution with ether, evaporate the solvent, dry carefully and weigh. 
The loss in weight represents the amount of cinnamyl cocain. 

Subject the residue to alkaline hydrolysis as follows: Use about 20 
mils N/10 alcoholic potash to every 0.1 gram of residue. Add to the mix- 
ture 20 mils distilled water and heat for half an hour on the water-bath, 
using a reflux condenser. Any volatile ester formed is, at this dilution, 
rapidly hydrolyzed. Evaporate alcohol, dilute with water to about 10 
mils, place in a separatory funnel and wash with ether. 

Add a slight excess of normal acid and extract three times with ether. 
Separate and evaporate ether extracts at a temperature below the boiling- 
point of ether. Add distilled water until a dilution of 1 : 500 is obtained 
and temperature kept at 14° C. Under these conditions the truxillic acid 
remains undissolved. Filter and wash thoroughly with water at 14°. 
Determine the benzoic acid in the filtrate by shaking out with ether and 
then separating the ethereal solution, adding to it in a separatory funnel 
a known volume of N/ 10 or N/ 50 alkali, extracting thoroughly and titrat- 
ing the excess of alkali with N/10 or N/50 acid. From the figures obtained 
the amount of benzoic acid and from that the amount of cocain can be 
calculated. 

Wash out the dish used in separating the benzoic from the truxillic 
acid with a small quantity of hot 90 per cent alcohol, pour through filter 
holding the rest of truxillic acid. Titrate with N/10 alcoholic potash. 
The figure obtained gives the amount of truxillic acid and from this the 
amount of truxillin can be determined. 

Factor for cocain 2.48. 

Factor for truxillin 2.22. 

Another procedure is as follows: Subject the crude alkaloids at once 
to alkaline hydrolysis. Evaporate the alcohol but not to dryness. Bring 
the products of hydrolysis into solution in water, acidulate and shake 
out with ether. Evaporate ether at a low temperature and treat the 
residue with water at 14°, diluting to 1 : 500. Filter and wash, leaving 
behind the truxillic acid, as before mentioned. 

Shake out the filtrate and washings with ether. Separate the ether, 
add a known volume of standard alkali, shake out and finally titrate the 
excess of alkali with standard sulphuric acid. This figure obtained repre- 
sents both the benzoic and cinnamic acids. Now add to the solution a 
slight excess of standard sulphuric acid. Add to this an excess of stand- 
ard bromine solution. (Bromine in potassium bromide.) Allow to stand 
with occasional agitation. Finally add potassium iodid solution, which 
removes the excess of bromine, and titrate the liberated iodine with stand- 
ard sodium thiosulphate. From the figures obtained the cinnamic acid 
present can be calculated and by referring to the titration figures obtained 



ALKALOIDS DERIVED FROM PYRROLIDIN 135 

with the mixed cinnamic and benzoic acids the amount of the latter may 
be determined. 

The truxillic acid left on the filter may be determined as in the pre- 
vious method. 

Factor for cinnamyl cocain 2.22. 

Cocain is so easily removed by ether or petroleum ether from a solu- 
tion made alkaline with ammonia that a determination of this alkaloid 
in products where it occurs as the salt is attended with little difficulty. 
The chief concern is to be sure that it is separated from the other alkaloids 
which may be present, and secondly, that in the process of manipulation 
no decomposition occurs. 

Atropin and quinin follow cocain closely in solubility and in making 
a determination of cocain in their presence resort must be had to other 
than solubility methods. 

In presence of quinin, cocain may be determined by heating both 
alkaloids under pressure in the presence of a dilute mineral acid at the 
temperature of the steam-bath for four hours at least. The benzoic acid 
resulting from the hydrolysis of the cocain can then be removed by ether 
and determined by titration. From the results obtained the amount of 
cocain may be calculated. If it is desired to determine both alkaloids, 
the residue given by the ether extract from ammoniacal solution should 
be weighed after drying. Then the mixed alkaloids may be subjected 
to the acid treatment above mentioned and the cocain determined from 
the benzoic acid. The difference will be the amount of quinin. 

• In order to determine the amount of cocain in pharmaceutical prepa- 
rations, caution must be observed in order that the alkaloid does not 
become decomposed during the manipulation. 

If the product is a liquid a weighed or measured quantity should be 
taken. If alcohol is present evaporate (in neutral solution if possible) 
until it is driven off. Then dilute the solution, render slightly acid with 
dilute sulphuric acid 2 per cent and filter if necessary into a separators 
funnel. Now shake out once or twice with ether, and if caffein is present 
make four extractions with chloroform. Then add ammonia until the 
solution is alkaline and shake out three times with petroleum or sulphuric 
ether. Combine the ether extracts, wash once with distilled water, and 
then filter the ether solution into a tared dish, carefully washing the filter 
paper and funnel. Dry at a low temperature and weigh. Then titrate 
the residue "with N/50 standard acid and alkali. 

If the residue is a mixture of coca alkaloids and it is desired to specif} r 
the actual amount of cocain the residue after weighing above should be 
treated according to Garsed's method. 

If the analyst is working with pills or tablets, these products should 
be carefully ground, and a weighed portion throughly extracted with 



136 ALKALOIDAL DRUGS 

alcohol. The alcoholic solution is then evaporated and the residue taken 
up with dilute sulphuric acid, filtered if necessary, into a separatory funnel 
and the above procedure followed. 

When working with an ointment or other product containing grease, 
place a weighed amount in an Erlenmeyer flask and add ether. Add 
water and sufficient ammonia to render the solution alkaline. Rotate 
the flask for fifteen or twenty minutes and then transfer the mixture to 
a separatory funnel, using caution to prevent any loss. Run off the aque- 
ous solution into another separatory funnel and shake it out twice more 
with ether. Combine all the ether extracts, shake out three times with 
2 per cent sulphuric acid, collecting acid washings in a fresh separatory 
funnel. Make alkaline with ammonia, shake out three times with petro- 
leum or sulphuric ether, filter into tared dish and weigh. 

COCA LEAF 

A systematic examination of the coca leaf has shown the presence of 
a small quantity of material volatile with steam to which the odor and 
flavor are partly due; from 2-5 per cent of wax; a little saponifiable fat; 
chlorophyll, from 5-10 per cent of a complex resin which contains a sub- 
stance contributing to the odor of the drug; from 8-15 per cent of a tannin- 
like substance; an appreciable quantity of ecgonin; the salts of a phos- 
phorus acid and unidentified organic acids amounting to about 10-20 per 
cent; complex carbohydrate-like substances; 8-10 per cent of proteins, 
cellulose, and allied substances. 

The nitrogenous material in coca leaf is quite considerable, and a por- 
tion of it only is represented by the alkaloids and ecgonin. 

The volatile material contains a little methyl salicylate. 

The tannin-like substance appears to be characteristic of coca. It 
is difficult to obtain in a pure and unaltered condition, owing to its sus- 
ceptibility to the action of reagents and heat. When first obtained it 
is readily soluble in alcohol and water, but it is easily converted to a form 
analogous to ellagic acid, which is insoluble in water. Its properties have 
been described, but as some authors have tested the soluble and others the 
insoluble form, the literature is confusing. Up to the present time the 
most important communication on cocatannic acid was made by C. J. 
H. Warden, 1 who worked with Indian-grown leaves. He describes a yel- 
low amorphous body, almost insoluble in water, which he claims has the 
formula C17H22O10. Investigation has since shown that the substance 
described was an anhydride or some transformation product of the tannin, 
and that probably it contained a small quantity of the tannin, which was 
the portion that Warden found soluble in water. 

1 Pharm. Journ. and Trans., 3d series, 1887-8, 985. 



ALKALOIDS DERIVED FROM PYRROLIDIX 137 

The separation of the tannin-like substance presents some difficulty, 
owing to the fact that it is readily decomposed or polymerized on heating 
and in contact with acids, and furthermore it is very hygroscopic. It 
can be partially removed from an acid aqueous liquid by means of ethyl 
acetate, and it is best removed from the leaves by first making a thorough 
extraction with anhydrous ether to dissolve coloring matter, fats, and 
waxes, and then percolating with 95 per cent alcohol. The alcohol dis- 
solves the tannin and resinous constituents, and on concentrating, render- 
ing anhydrous with sodium sulphate and precipitating by pouring into 
a large volume of chloroform, the tannin is obtained as a yellowish-brown 
precipitate, which can be filtered off and dried in vacuo over sulphuric acid. 

As first obtained, this yellowish substance will be completely soluble 
in water, but on standing the insoluble form gradually develops. An 
aqueous solution gives a deep olive-green color with ferric chloride, and 
the same color and an olive-green precipitate with ferric acetate. It gives 
a yellow precipitate with bromin water, and a white precipitate with 
silver nitrate, the latter turning gray on standing, leaving the supernat- 
ant liquid colorless. With gelatin no precipitate is obtained, even in the 
presence of sodium chloride, but on adding sulphuric acid in the presence 
of gelatin a white precipitate is thrown out. Cinchonin sulphate produces 
a slight but definite precipitate. Potassium ferricyanide and ammonia 
give a deep brownish-yellow color with a reddish cast. Lead acetate 
gives an orange or reddish-yellow precipitate. Lime water produces a 
yellow color, but no precipitate. Xo observable reaction is obtained 
with starch, antipyrin, barium chloride, magnesia mixture, ammonium 
molybdate, alum, or borax. Reduction occurs with permanganate and 
to a slight extent with Fehling's solution. 

Attempts to determine the character of the tannin have as yet yielded 
no information on which definite conclusions can be based. 

SYNTHETIC ANESTHETICS 

The advance of synthetic chemistry has resulted in the evolution of 
a number of artificial anesthetics, some of winch have assumed consider- 
able importance, and as they are often substituted for cocain they will 
be considered at this point. 

Most of these substances have well-defined characteristics, they are 
offered in the pure state or in mixtures from which the}' can be removed 
by simple means, so that then identification should present no difficult}', 
and it is not likely that the analyst will encounter more than one individual 
at a time. 

Beta eucam, holocain, eupthalmin, novocain, the orthoforms, stovain, 
cliloretone, acoin, alypin, and anesthesin are being employed to a con- 
siderable extent. 



138 ALKALOIDAL DRUGS 

Most of them are basic in character, dissolving readily in acids and 
removable from alkaline solutions by immiscible solvents. 

These anesthetics fall into several different groups, the members of 
each group resembling each other to a greater or less extent. 

Thus the eucains and eupthalmin are derivatives of gamma-oxymethyl 
piperidin; holocain and acoin may be considered derivatives of anilin 
antipyretics; the orthoforms, anesthesin and subcutin, are derivatives of 
benzoic acid; the derivatives of glycocollamido carbonic acid are repre- 
sented by nirvanin; the derivatives of guaicol include brenzcain, guai- 
sanol, and guaiacyl; alypin, novocain, and stovain from a fairly well- 
defined group; and chloretone is trichlor tertiary butyl alcohol. 

THE EUCAINS 
Alpha Eucain 

The hydrochloride of benzoyl-n-methyl-tetramethyl-gammaoxy-piperi- 
dinecarboxylicmethyl ester. 

It has almost entirely been displaced by beta eucain. 

The free base is precipitated from its aqueous solutions by ammonia, 
alkali, and alkali carbonates; it forms a pasty mass which quickly becomes 
crystalline. 

If 5 mils of a 1 per cent solution of alpha eucain is treated with 3 drops 
5 per cent chromic acid a beautiful yellow precipitate appears immedi- 
ately. 

If 5 mils of a 1 per cent solution is treated with 30 mils 10 per cent 
potassium iodid solution, a milkiness appears and after a short time color- 
less plates of eucain hydrogeniodid form and separate. 

Neither of these two reactions is given by cocain. 

Beta Eucain C 5 H 7 N(CH3)3(C6H 5 COO)HCl 

The hydrochloride of benzoyl-vinyl-diaceton-alkamin, or 2, 6, 6-trime- 
thyl-4-benzoyl-piperidin. 

The salt forms a crystalline powder soluble 1-25 in water at 15° C, 
more soluble in warm water. It melts at 268° C. 

The free base is precipitated by ammonia, alkalies, and alkali carbon- 
ates, and is liquid at the ordinary room temperature 

A solution of the salt gives precipitates with Mayer's reagent, iodin 
in potassium iodide, phosphomolybdic acid, phosphotungstic acid, potas- 
sium chromate, potassium bismuth iodide and picric acid. No precipi- 
tate occurs with mercuric chloride unless the solution is concentrated, 
and the precipitate is soluble in excess of the reagent. With chromic 
acid a precipitate is given in concentrated solution, it is amorphous and 
soon agglomerates and dissolves in strong hydrochloric acid. When a 






ALKALOIDS DERIVED FROM PYRROLIDIN 139 

1 per cent solution is treated with chlorine water a dense white turbidity 
occurs, differing from cocain which gives no precipitate. 

A crystalline precipitate is thrown down by platinic chloride, which 
has a characteristic form under the microscope. The precipitate with 
gold chloride is amorphous. 

When its acid solution is treated with ammonia a white precipitate 
is formed which is readily soluble in petroleum ether. 

Parsons 1 has studied the reactions of the eucains with special refer- 
ence to distinguishing them from cocain. 

Potassium iodide (1 : 10) gives, in even moderately dilute solutions of 
a-eucam hydrochloride, a white silky and glistening precipitate. This 
precipitate has much the same appearance as the one obtained when stan- 
nous chloride is added to a cold dilute solution of mercuric chlorid. 
/3-eucain and cocain give no reaction. 

" Ammonia, even in dilute solution, precipitates the bases a- or /3- 
eucain or cocain, but a-eucain is almost insoluble in excess. In 1 per 
cent solution the white precipitate is at once thrown down, and in the 
case of /3-eucain or cocain dissolves immediately on addition of about their 
own volume of strong ammonia, a-eucain, so precipitated, can be diluted 
at least ten times with strong ammonia without solution. In stronger 
solutions the difference still exists, but is not so easily recognized. A 3 
per cent solution of /3-eucain or cocain requires about five times its own 
volume of ammonia to be dissolved, and stronger solutions much in pro- 
portion to the per cent present. In other words, a strong solution of 
ammonia will dissolve about \ of 1 per cent of the bases /3-eucain or cocain, 
while it will dissolve but a very small fraction of a per cent of a-eucain. 
In dilute solutions this is a very characteristic reaction for a-eucain and 
strong solutions are, of course, very easily rendered dilute for the test. 

Potassium dichromate, in strong solution, added drop by drop to 
a 0.5 per cent solution of a-eucain, begins to throw down a fine lemon- 
yellow precipitate after addition of 1 or 2 drops. The precipitate is then 
much increased by 1 or 2 drops of strong hydrochloric acid, and is then 
quite soluble, dissolving only after several times diluting the volume of 
the solution. With stronger solutions the precipitation takes place at 
once, the first drop giving a more and more permanent precipitate as the 
solution grows stronger. The precipitate is notably insoluble in either 
water or hydrochloric acid. More dilute solutions will show no precipi- 
tate or only after addition of hydrochloric acid. Cocain, 1 per cent, solu- 
tion, is not precipitated by potassium dichromate, but the addition of 1 
or 2 drops of concentrated hydrochloric acid throws down a yellow pre- 
cipitate easily soluble in very slight excess of hydrochloric acid on dilu- 

1 American Journal of Pharmacy, 1902, p. 198, Jour. Amer. Chem. Soc, 1907, 
p. 885. 



140 ALKALOIDAL DRUGS 

tion of the solution with water. Weaker solutions do not precipitate, 
while stronger solutions precipitate at once. The precipitate, however, 
is easily soluble as before. /3-eucain acts like cocain. The precipitate in 
all cases is lemon-yellow. The a-eucain precipitate is quite crystalline. 
All three may throw down a small amount of a yellow colloidal precipitate 
which sticks to the side of the test-tube and dissolves but slowly, although 
this in nowise interferes with the test, and does not take place if reagents 
are added slowly. While this test depends upon the very much greater 
insolubility of the a-eucain salt, the non-precipitation in dilute solutions 
of a certain strength until after the addition of hydrochloric acid is quite 
characteristic for all. The correct strength is about 0.5 per cent solu- 
tion of a-eucain and about 1 per cent for /3-eucain and cocain. In the 
case of cocain and /3-eucain, the test may be conveniently applied by pre- 
cipitating a stronger solution than 1 per cent with potassium dichromate 
solution, diluting carefully with water until precipitate just dissolves. On 
addition of a drop of concentrated hydrochloric acid the precipitate will 
at once reform. This cannot be done with a-eucain, for precipitate once 
formed it is difficult to get it to dissolve at all. 

Chromic acid (1 : 20) acts similarly to the dichromate. 

If a small amount of cocain hydrochloride be rubbed up with dry mer- 
curous chloride (calomel) and then moistened with alcohol, it rapidly turns 
to a grayish black, a-eucain hydrochloride becomes slowly a dark gray. 
0-eucain hydrochloride is not affected. 

Platinic chloride throws down slowly a yellow crystalline precipitate 
from a 1 per cent solution of cocain hydrochloride, which is insoluble in 
hydrochloric acid, a- and /3-eucain hydrochloride in 1 per cent solution 
are not altered. In stronger solutions all three hydrochlorides are immedi- 
ately precipitated by platinic chloride, but the cocain precipitate is not 
soluble in hydrochloric acid, while the precipitates by either eucain are 
at once dissolved. 

Cocain solutions almost always cause mydriasis; /3-eucain does not 
dilate the pupil. 

The lactate of /3-eucain is a white non-hygroscopic powder melting at 
152-155° C. and readily soluble in water and alcohol. The base is pre- 
cipitated by ammonia and alkalies and responds to the usual character- 
istic reactions. 

If 1 gram of /5-eucain lactate is warmed with a few drops of dilute sul- 
phuric acid and 1 mil of potassium bichromate (1 : 10) the odor of acetalde- 
hyde is evolved. 

Eupthalmin Hydrochloride 

The hydrochloride cf phenyl-glycolyl-n-Methyl-beta-viny!-diaceton» 
alkamin. 



ALKALOIDS DERIVED FROM PYRROLIDIN 141 

It is the mandelic acid derivative of beta eucain, and possesses marked 
mydriatic properties. It is not an anesthetic. 

The salt forms a colorless crystalline powder. Its solution gives pre- 
cipitates with Mayer's reagent and with iodine in potassium iodide, phos- 
phomolybdic and phosphotungstic acids. No precipitate occurs with 
potassium chromate, nor with platinic chloride or chlorine water. 

When evaporated with nitric acid a yellow residue is left which on 
treatment with alcoholic potash gives off an odor of benzaldehyde and red 
oily drops appear. 

On treating with a solution of molybdic acid in sulphuric acid no color 
appears at first, but on standing the outer rim becomes blue. 

Holocain Hydrochloride 

Holocain. Para-diethoxy-ethenyl-diphenylamidin. 

CH3C- (NC 6 H40C2H5)NHC 6 H40C2H5 

The base is a condensation product of para-phenetidin and acetphen- 
etidin and forms white crystals melting 121°; insoluble in water. 

The hydrochloride is soluble in water and alcohol. 

An acid solution of holocain gives a white precipitate with ammonia 
which is slightly soluble in petroleum ether but readily soluble in ether. 
Precipitates are produced by the ordinary alkaloidal reagents. An 
aqueous solution acidified with hydrochloric acid gives a white precipitate 
and with mercuric chloride, and with calcium hypochlorite a violet pre- 
cipitate is obtained, soluble in ether, and imparting to it a red color. 

When evaporated with nitric acid the base leaves a yellow residue 
which turns red on the addition of alcoholic potash and gives off a dis- 
agreeable odor. 

Acoin 
Di-para-anisyl-monophenetyl-guanidin-hydrochloride. 
(CH 3 OC6H 4 NH)2CNCoH 4 OC2H5 +HC1 

Acoin is a white crystalline powder — melting-point 176°, soluble in 
water. 

Its solutions are precipitated by the ordinary alkaloidal reagents and 
with bromine water a dirty-yellow curdy precipitate forms which turns 
to purple on adding ammonia dissolved in chloroform. 

Immediate reduction takes place with permanganate. 

The base is somewhat soluble in petroleum ether, and readily soluble 
in ether. It gives a deep red color with nitric acid and on treating the 
evaporated product with alcoholic potash an agreeable odor is given off. 



142 ALKALOIDAL DRUGS - 

The Orthoforms 
Orthoform. — 

Para-amido-meta-oxybenzoic-methyl-ester. 

C 6 H3(COOCH3)NH 2 OH 1-4-3 

It is a white, odorless, tasteless, crystalline powder; slightly soluble 
in water, readily soluble in alcohol, and melting 118-120° C. 
Its solution in acetic acid gives a green color with PbCb. 

Orthoform " New ".— 

Meta-amido-para-oxybenzoic-methyl-ester, 

C 6 H3(COOCH3)NH 2 OH, 1-3-4. 

Fine white powder, difficultly soluble in water, readily soluble in 5 to 
6 parts of alcohol, soluble in ether 1-50, and alkalies. 

It occurs in two modifications, sometimes crystallizing out of chloro- 
form in quadratic plates melting at 110-112° C. As a general thing, how- 
ever, it crystallizes in shining needles melting at 142°. The lower melt- 
ing modification is transformed to the higher on fusion. 

Its solutions are neutral. A cold aqueous solution is colored red by 
ferric chloride, and on heating the red is changed to green. On boiling 
the aqueous solution, orthoform is decomposed into methyl alcohol and 
paraoxybenzoic acid. 

If 0.1 gram is dissolved in 2 mils of water with help of a little dilute 
sulphuric acid, and a few drops of sodium nitrite solution added, the solu- 
tion becomes yellowish red and a yellow precipitate comes down which 
becomes intensely red in contact with the air. 

With concentrated nitric acid a blue color changing to red occurs. No 
odor develops on the subsequent addition of alcoholic potash. The other 
orthoform gives a green color with nitric acid. 

It gives precipitates with phospho-molybdic and phosphotungstic acids. 
With bromine water a yellowish green precipitate is obtained differing 
from most of the other synthetic anesthetics which give a white or a 
yellowish precipitate. On subsequently adding ammonia the green pre- 
cipitate gives way to a dark-red solution. It does not give precipitates 
with either Mayer's or Wagner's reagents. 

It is practically insoluble in petroleum ether, very slightly soluble in 
chloroform, more readily in ether. 

The Orthoforms combine with chloral to form tasteless products of 
great hypnotic action. They are difficultly soluble in water but readily 
so in alcohol and ether and on warming with mineral acids are broken up, 
chloral being liberated. 



ALKALOIDS DERIVED FROM PYRROLIDIN 143 

Anaesthesin 
Ethyl ester of paramido benzoic acid. 

C6H4NH2COOC2H5 

It forms a white odorless, tasteless powder, melting 89-91° C. It is 
sparingly soluble in cold water, readily soluble in hot water and in organic 
solvents, except petroleum ether, in which it dissolves but sparingly. It 
dissolves readily in fixed oils and fats. It is removed by solvents from 
acid solution. 

0.1 gram anesthesin treated with 100 mils of water and a little hydro- 
chloric acid followed by a few drops of sodium nitrite solution and an equal 
quantity of beta-naphthol solution results in the production of an intense 
cherry red color changing to orange with acids. 

On boiling with alkalies it is decomposed into paramido-benzoic acid 
and ethyl alcohol. 

It gives precipitates with the ordinary alkaloidal reagents, except 
Mayer's reagent and tannic acid. No precipitate is given with potassium 
chromate until the solution is acidified, when a brown deposit takes place 
with reduction. Immediate reduction occurs with potassium perman- 
ganate. A dark greenish-black residue is left on evaporation with nitric 
acid and no odor is given off with alcoholic potash. 

Propaesin 
Propylester of paramido benzoic acid. 

CGH4NH2COOC3H7 

This substance occurs as a white bulky crystalline powder, neutral to 
litmus and having a melting temperature 74-76°. It is slightly soluble 
in water, and with difficulty in dilute sulphuric acid, unless the liquid is 
warmed, but it is readily soluble in alcohol, chloroform, and ether. 

An acid solution of propaesin does not give a precipitate with Mayer's 
reagent but other usual alkaloidal reagents, Wagner's, phosphomolybdic 
acid, phosphotungstic acid give immediate precipitates. With potassium 
chromate no reaction occurs, but after adding an equal volume of con- 
centrated hydrochloric acid, the mixture darkens and a dirty brown pre- 
cipitate comes out. The same reaction occurs in the case of 5 per cent 
chromic acid and hydrochloric acid. Potassium permanganate, when in 
dilute solution, is at first decolorized when added to an acid solution of 
propaesin; but as soon as an excess is present the permanganate is reduced. 
Bromin water gives a white precipitate and no change occurs when 
ammonia is subsequently added. An aqueous solution of its hydrochlo- 
ride gives precipitates with platinic chloride and with palladium chloride. 



144 ALKALOIDAL DRUGS 

No characteristic color reactions occur with oxidizing agents, nor with 
mineral acids. Ammonium vanadate gives a purple color soon chang- 
ing to brown and gradually fading into gray, the best results apparently 
occurring when the propaesin is in considerable excess. When treated 
with nitric acid and evaporated over the steam-bath, the residue gives 
no characteristic odor when alcoholic potash is added. 

Propaesin is removed from its acid solutions by ether and by chloro- 
form, and from its alkaline solutions petroleum ether will separate it 
readily, though this solvent removes it but slightly from acid solutions. 

When heated with a solution of potassium hydroxide it melts and forms 
an oily layer. If this mixture is boiled, propyl alcohol is evolved which 
may be recognized by its odor, and the alkaline liquid will contain par- 
amido benzoic acid. The latter may be separated by neutralizing with 
mineral acid. 

Subcutin 
Para-phenolsulphonic acid-ethyl ester of para-amidobenzoic acid. 
CeH^COOCs^NHsSOsHCeHiOH 

The paraphenol sulphonic acid derivative of anesthesin. 

It is a white crystalline powder melting-point 195.6°. This product 
is not readily soluble in cold water, but on warming the liquid it dissolves 
readily, the odor of ethyl benzoate being very marked. The aqueous solu- 
tion obtained either in the cold or on warming is acid to litmus. It is 
readily soluble in ether, but does not dissolve to any great extent in chloro- 
form and petroleum. 

It is completely removed from a solution acidulated with sulphuric 
acid by ether and partly by petroleum ether. From ammoniacal solu- 
tions it is much less readily given up to solvents. 

An acid solution gives no precipitate with Mayer's reagent, but it 
reacts at once with iodine solution, the precipitate soon separating out 
in oily drops. Precipitates are given by picric acid, palladium chloride, 
phosphotungstic and phosphomolybdic acids and bromin water. Tan- 
nic acid gives no precipitate. Chromic acid solution produces a turbidity 
which is not changed on the addition of hydrochloric acid, and on standing 
a brown precipitate gradually settles. Potassium chromate gives no pre- 
cipitate but on adding hydrochloric acid a deep red to brown color appears 
and a brown precipitate is found. Immediate reduction occurs with potas- 
sium permanganate. Ferric chloride solution in small amount produces 
a brownish purple but the color changes to a yellowish on adding more 
of the reagent. This reaction is not given by anesthesin. Formaldehyde 
sulphuric acid acting directly on subcutin gives no color at first, but a 
salmon shade soon develops, which gradually darkens to red then becomes 



ALKALOIDS DERIVED FROM PYRROLIDIN 145 

brownish red and finally brown. Ammonium vanadate produces immedi- 
ately a beautiful green changing at once to blue and disappearing in a 
moment. Neither of these reactions is given by anesthesia. With sul- 
phuric acid and bichromate a green color appears at once. On evapor- 
rating to dryness with nitric acid a brownish-yellow residue is left. Alco- 
holic potash becomes blood red when added to this product and an agree- 
able odor differing somewhat from ethyl-benzoate is given off. 

Cycloform. Isobutyl paramidobenzoate 

C 6 H4(NH2)COOCH 2 CH(CH3)CH3 

Cycloform is a white crystalline substance, melting 65°, slightly soluble 
in water, but dissolving readily in alcohol, ether, and benzol. When heated 
with concentrated sodium hydroxide it evolves isobutyl alcohol, recog- 
nized by its odor. 

Nirvanin 

The hydrochloride of diethyl glycocoll-p-amido-o-oxybenzoic acid- 
methyl ester. 

HC1(C 2 H 5 )2N CH 2 CONHC 6 H3(OH)COOCH3 

It forms white prisms melting at 185° C, soluble in water and alcohol. 
The base is precipitated by sodium hydrate or ammonia as a white solid, 
soluble, in excess, but in the case of ammonia a precipitate reappears on 
warming. 

Its solution gives precipitates with all the ordinary alkaloidal reagents, 
and a violet color with ferric chloride. 

On evaporating with nitric acid a red-colored residue is left which gives 
no characteristic odor on the addition of alcoholic potash. 

Alypin 

The hydrochloride of benzoyl-tetramethyl-diamino-ethyl isopropyl 
alcohol. 

(CH3)2NCH2C(C2H 5 ) (C 6 H 5 00) (CH 2 N(CH 3 ) 2 )HC1 

Alypin is a white crystalline powder melting 169°. It forms a neutral 
solution in water which is not rendered turbid by sodium bicarbonate. 
Its solutions give precipitates with Mayer's and Wagner's reagents, with 
phosphomolybdic and phosphotungstic acids and with bromin water, but 
no precipitate occurs with potassium chromate. Potassium bichromate 
produces a yellow crystalline precipitate soluble in hydrochloric acid. 
Potassium permanganate produces a violet crystalline precipitate which 
turns brown on standing. 



146 ALKALOIDAL DRUGS 

On the addition of alcoholic potash to a residue obtained by the evapo- 
ration of alypin with nitric acid, a disagreeable odor is given off. 

The free base is a colorless, strongly alkaline oil which is somewhat solu- 
ble in water. 

When warmed with sulphuric acid at the temperature of the water- 
bath, and then diluted with a little water, the odor of ethyl benzoate is 
evolved. 

Stovain 

Ethyl-dimethyl-amino-pentanol-benzoyl-hydrochloride. 

C 6 H5COO(CH3)CC2H5CH2N(CH3) 2 HCl 

Stovain forms small glassy plates, melting 175° C, soluble in water, 
alcohol, and acetic ether, but almost insoluble in ether. The free base 
is precipitated by alkalies, and may be removed from solution by immiscible 
solvents, petroleum ether dissolving it readily. 

It is not precipitated by potassium iodide, but is thrown down by all 
the other alkaloidal reagents. It is precipitated by sodium bicarbonate 
and in this respect and in its action with potassium iodide it differs from 
alypin. 

The residue obtained on evaporation with nitric acid gives off an odor 
of ethyl benzoate and isonitrile when treated with alcoholic potash. 

0.1 gram of stovain treated with 5 mils sulphuric acid and heated for 
five minutes at 100° C. gives off the odor of ethyl benzoate on adding 5 
mils water. 

Novocain 

The hydrochloride of para-amino-benzoyl-diethyl-amino ethanol. 

C 6 H4NH2(l)COOC2H4N(C2H 5 )2(4)HCl 

The hydrochloride is a crystalline salt soluble in water 1-1 and in 
alcohol 1-30. Melting-point 150-155°. 

Caustic alkalies and alkali carbonates precipitate the base as an oily 
mass which crystallizes w T hen cool. Sodium bicarbonate does not pre- 
cipitate the base. From ether the base crystallizes in the anhydrous 
state, melting at 58-60°, while from alcohol it crystallizes with 2H2O, melt- 
ing at 51°. 

It gives precipitates with alkaloidai reagenxs and is soluble in sulphuric 
and hydrochloric acids without color. 

0.1 gram of novocain in 5 mils water treated with 2 drops hydro- 
chloric acid and 2 drops sodium nitrite solution, gives a scarlet red pre- 
cipitate when added to a solution of beta naphthol. 

On evaporating with nitric acid a yellowish red residue is left which 



ALKALOIDS DERIVED FROM PYRROLIDIN 147 

on treatment with alcoholic potash becomes red and gives off the odor of 
isonitrile. 

Potassium chromate gives no precipitate. On adding hydrochloric 
acid reduction to a green color occurs which becomes red on standing. 

Novocain when mixed with mercurous chloride and moistened with 
alcohol turns dark similarly to cocain. 

If 0.5 gram of novocain in 2 mils water be treated with potassium 
bichromate solution drop by drop a precipitate is formed which dissolves 
on shaking. 

Chloretone 
Trichlor-tertiary-butyl-alcohol. 

(CH3) 2 C0HCC1 3 

Chloretone occurs in snow-white crystals having a camphoraceous odor 
and taste. It is volatile with steam. It is soluble in chloroform, acetone, 
alcohol, ether, petroleum ether, glacial acetic acid, glycerin, fixed and 
volatile oils, also in warm water to the extent of 1 per cent, but on cool- 
ing a portion crystallizes out, the cold saturated solution containing 0.8 
per cent. It possesses a peculiar property of sliding and rotating about 
on the surface of water. 

When applied to the tongue it causes first a slight peppery sensation, 
and then a numbness, the latter, however, being much less pronounced 
than that caused by cocain and unaccompanied by the slippery feeling. 

Chloretone of the formula (CHs)2COHCCl3 has a melting-point of 
97° C. It forms solid solutions with water, these products having melting- 
points down to 75°, depending on the amount of water present, and it 
is in some of these latter forms that it occurs on the market. 

Its solution in acid does not give precipitates with the ordinary alka- 
loidal reagents. 

It is soluble with decomposition in strong sulphuric acid. 

With cold dilute potassium hydrate solution alpha-chlorisobutyric acid 
results and with concentrated potash, acetone, chloroform, and methyl 
acrylic acid. It is soluble in dilute ammonia, from which solution it may 
be removed by means of immiscible solvents. 

Deniges 1 describes the following qualitative reactions for chloretone 
and also gives a method for its quantitative determination: 

If 5 mils of a 5 per cent alcoholic solution of chloretone be boiled 

with 1-2 mils of solution of sodium hydroxide and allowed to cool, the 

clear solution produced becomes turbid on addition of mercuric sulphate; 

or, if instead of mercuric sulphate a few drops of fresh sodium nitro- 

J Rep. de Pharm., 1905, No. 11. 



148 ALKALOIDAL DRUGS 

prusside are added, followed by acetic acid in slight excess, the well-known 
carmine color of Legal's acetone reaction is developed. Ammoniacal silver 
nitrate is decomposed by solution of chloretone in the cold; Fehling's 
solution is reduced by it on boiling. The quantitative determination by 
titration is effected by adding to 10 mils of a 1 per cent solution of chlore- 
tone, in diluted alcohol, 1-2 mils of solution of sodium hydroxide, free 
from chlorine, and 10 mils of alcohol, and heating the mixture to boiling. 
After cooling, 1-2 mils of nitric acid (1.39) are added, the liquid is adjusted 
with water to 100 mils and the sodium chloride formed is titrated in the 
usual manner with silver nitrate, using potassium chromate as indicator 
and calcium carbonate to render the liquid milky. One mol. of chlore- 
tone forms 3 mols. of sodium chloride. 

Chloretone should always be looked for in remedies designed to relieve 
seasickness. 

Guaiasanol. " Gujasanol " 
Diethylglycocoll guaiacol hydrochloride. 

C 6 H4(OCH3)OCOCH 2 N(C2H5)2HCl 

Gujasanol forms white prismatic crystals, melting 183-184° C, readily 
soluble in water, and the odor of guaiacol is apparent. 

Mayer's reagent gives a yellowish white precipitate and Wagner's 
throws out a brown precipitate which soon becomes oily and sticks to the 
sides of the container. It gives a white precipitate with ammonia which 
is readily soluble in petroleum ether and remains a colorless oily liquid 
on evaporating the solvent. 

Brenzcain 
Guaiacol benzyl ester. 
Pyrocatechin methyl benzyl ester. 

C6H4OCH3OCH2C6H5 

Brenzcain forms colorless crystals melting 62°, spluble in alcohol, ether, 
and oils, but insoluble in water. On warming with hydrochloric acid 
guaiacol results and with potassium permanganate and sulphuric acid 
benzaldehyde is formed. 

Guaiacyl 

Calcium ortho guaiacol sulphonate. 

(C 6 H3(OH)(OCH 3 )S03)2Ca 

Gaiacyl is a grayish-brown powder readily soluble in water and alcohol. 
Its aqueous solution is violet red. 



CHAPTER VI 

ALKALOIDS DERIVED FROM QUINOLIN 
THE CINCHONA ALKALOIDS AND THEIR DERIVATIVES 

Cinchona bark and certain of the alkaloids contained therein, have 
an extended and important use in medicine. The drug itself, depending 
on the variety, may contain a number of different bases, and while the 
list is extensive numerically, the actual number with which the drug 
analyst will be concerned is small, being limited, except in rare instances, 
to four or perhaps five individuals, quinin, quinidin, cinchonin, cinchoni- 
din, and cuprein. Pictet mentions twenty-one alkaloids in his list; Chick, 
in the new edition of Allen, gives thirty-one and later mentions homo- 
quinin, which is described by Pictet in his original list, so the number may 
be left at thirty-two. Pictet divides the bases into six main groups accord- 
ing to their composition and according to the nature of the decomposition 
products which are produced by the action of mineral acids. Each of the 
first three groups contains a subgroup which differs from the main group 
only in possessing a slightly greater amount of hydrogen. Chick classi- 
fies the alkaloids in five groups as follows: 

1. Cinchonin Class. 

Paricin, Ci 6 HisON2 

Cinchotin or Hydrocinchonin 

Cinchamidin or Hydrocinchonidin > C19H24ON2 . 

Cinchonamin 

Cinchonin 



Cinchonidin 
Homocinchonidin 
Cinchonicin 
Paytin 
Paytamin 
2. Quinamin Class. 



C19H22ON2 
C 2 iH 2 40N 2 



Quinamin . M 

^ . . \ C19H24O2JN2 
Conqumamm 

Javanin 

Cuprein, C19H22O2N2 

149 



C22H2604N2 



150 ALKALOIDAL DRUGS 

3. Quinin Class. 

Hydroquiiiin I r „ n M 

Quinin 

Quinidin > C20H24N2O2 

Quinicin J 

4. Cusconin Class. 

Chairamin 

Conchairamin 

Chairamidin 

Conchairamidin 

Concusconin 

Aricin 

Cusconin 

Cusconidin 

5. Anhydro bases. 

Dicinchonicin 

Diquinicin 

Homoquinin 

In addition to these bases there have been reported a number of acid 
and neutral bodies including quinic, quinovic, caffeic, oxalic, and certain 
tannic acids, quinovine, quinia red, quinovic red, cinchocerotine, cinchol, 
cupreol, cholesterol, etc. 

CINCHONA BARKS 

The drugs containing these alkaloids are obtained from several trees 
belonging to the genera Cinchona and Remijia (family of the Rubiaceae). 
Many species of Cinchona have been described, but those yielding bark 
of any practical importance are limited. Of the varieties of commercial 
importance may be mentioned pale, crown or loxa bark from Cinchona 
officinalis; yellow Peruvian or Calisaya bark from C. calisaya and hybrids; 
red bark from C. rubra and C. succirubra and its hybrids, and containing 
a high percentage of cinchonidin; pitayo bark from C. Patayensis; Colum- 
bian or Carthagina bark from C. lanceolata, C. lancifolia, C. cordifolia, 
etc.; Ledger bark from C. Ledgeriana, very rich in quinin; and cuprea 
bark from Remijia pedunculata. The value of a bark depends on its alka- 
loidal content and this is extremely variable, barks having as high a con- 
tent as 15 per cent have been reported and from tins it runs down to a 
fraction of a per cent. Under the present system of cultivation the trees 
are not destroyed when the bark is gathered, a part only is removed, the 
remainder being left intact and the stem is then covered with moss under 

ch new bark forms rapidly. Quinin, cinchonin, and cinchonidin are 



ALKALOIDS DERIVED FROM QUINOLIN 151 

the bases most frequently found, quinidin is less common and is never in 
large amount 

Cinchona and its alkaloids probably enter into a greater number of 
combinations and have a wider field of application than any other drugs 
used in medicine. Their properties are tonic, febrifugal, and antiperiodic, 
and hence they are recommended in malarial troubles and in convalescence. 
The classes of pharmaceuticals containing them include a great variety 
of pills, tablets, elixirs, wines, syrups, capsules, and bitters. 

First taking up cinchona extract we find that this product is used in 
a plain elixir of calisaya; in combination with bismuth and ammonium 
citrate, with pyrophosphate, with strychnin and pepsin, either altogether 
or with one or more; with beef extract and iron oxy chloride in the beef, 
iron, and wine products ; with malt extract ; and in various alcoholic prod- 
ucts known as bitters such as Dubonnet, Quinquina, Ferro China Bisleri, 
and Quinin whisky types. 

Quinin sulphate occurs in pill and tablet formula? and in elixirs and 
bitter tonics combined with iron pyrophosphate and strychnin sulphate. 
Among the pills and tablets may be mentioned combinations of quinin 
sulphate with strychnin, reduced iron, and arsenous acid used in malarial 
conditions in which will be found at times aloes, Podophyllum resin and 
Gelsemium extract; iron and quinin citrate; iron, quinin, and strychnin 
citrate; quinin sulphate, arsenous acid, strychnin, aconite, and morphin 
for neuralgia; phosphorus, iron, either reduced or as ferrous carbonate, 
and quinin, with and without strychnin and sometimes with Digitalis 
and ipecac; quinin, arsenous acid, gentian, and atropin sulphate; quinin 
sulphate and Capsicum or oleoresin black pepper; iron, quinin, and zinc 
valerianates, sometimes with gold and sodium chloride and sumbul root; 
Warburg tincture containing quinin sulphate, rhubarb, angelica seed, 
elecampane, saffron, fennel, gentian, zedoary root, cubeb, myrrh, white 
agaric, camphor, with or without aloes; bronchitis tablets of belladonna, 
ipecac, opium and quinin sulphate; coryza tablets of camphor, quinin, 
morphin, and atropin sulphate; or of similar composition with ammonium 
chloride and no atropin; rhinitis tablets of camphor, belladonna, and 
quinin sulphate; acetanilid and quinin sulphate; acetanilid, caffein, sodium 
bicarbonate, sodium bromide, and quinin sulphate; ergot, Digitalis, and 
quinin sulphate; hypophosphites compound containing the hypophos- 
phites of quinin, calcium, iron, sodium, potassium, manganese, and strych- 
nin, sometimes with guaiacol; the same bases are also presented as phos- 
phates; rheumatic tablets composed of quinin sulphate, extracts of 
Colchicum, colocynth, Hyoscyamus, opium, and mercury; cold tablets com- 
posed of quinin hydrobromide, aloin, Capsicum, calomel, aconite, ipecac, 
and opium, sometimes with cascara; inspissated oxgall, pancreatin, colo- 
cynth, Nux Vomica, Taraxacum and quinin sulphate; and quinin sulphate 



Ib2 ALKALOIDAL DRUGS 

or bisulphate alone in tablets and capsules of various strengths. Quinin 
and urea hydrochlorate are used in hypodermatic tablets. The elixir 
formulae often include pepsin and bismuth and ammonium citrate and the 
phosphate syrups will contain the phosphates of the alkaline earth and 
alkali bases. 

Quinidin will be found substituted for quinin and it is well to look for 
the former in all products which especially claim to be free from quinin. 

Cinchonidin sulphate is combined with iron, arsenic, and strychnin 
in tablets and sometimes replaces quinin in the other formulas mentioned. 
It has been sold in an aphrodisiac compound mixed with Coca, phosphorus, 
Nux Vomica and bromides. It will be found in tonic pills with Xantho- 
oxylum, dogwood and Capsicum, and is also marketed alone as is also 
cinchonidin salicylate. 

Cinchonin sulphate has the same remedial properties as quinin sulphate 
and may be met with at any time, though its use is much limited compared 
to quinin. 

Cinchonin 

This alkaloid differs from quinin in lacking a methoxyl group, the con- 
stitutional formula accredited to it at present being 



. ,\ 

H2C CH2 CH — CH=CH2 

1 1 1 
ch 2 — COHCH2CH2 

H I \ 

C C X N- 

/\ /X 

HC C CH 

I II I 

HC C CH 

Yh X n/ 

It is easily crystallized and melts from 250-265°, depending on its purity, 
and may be distilled unchanged in a current of hydrogen, ammonia, or 
in vacuo. It is somewhat soluble in boiling water, but almost insoluble 
in cold water, somewhat soluble in chloroform, benzol, amyl alcohol, and 
alcohol, and difficultly soluble in ether, especially when the solution and 
solvent are cold. It is a fairly strong diacid and bitertiary base, and 
both the alkaloid and its salts are dextrorotatory. 

Cinchonin yields several isomers when acted upon by different chemical 
reagents. Among these may be mentioned cinchonidin, its stereoisomer, 



ALKALOIDS DERIVED FROM QUINOLIN 153 

which also occurs naturally, and cinchonicin, obtained by heating the 
alkaloid with very dilute sulphuric acid to 130° C. 

The double bond in the side chain facilitates the addition of chlorine 
and bromine, giving in the cold, addition products. The dichloride and 
dibromide are crystalline, somewhat unstable, and behave as diacid bases. 
It also gives monobenzoyl, and monoacetyl derivatives due to the hydro- 
xyl group. 

The acid solutions of cinchonin are not fluorescent and the alkaloid 
does not give the thalleoquin test, thereby differing from quinin; it gives 
no well-defined characteristic color tests, but is precipitated by all of the 
ordinary alkaloidal precipitants including Mayer's and Wagner's reagents, 
phosphomolybdic and phosphotungstic acids, tannin, bromin water, gold 
chloride, platinic chloride, mercuric chloride, picric acid, potassium bis- 
muthic iodide, and sodium carbonate; with potassium ferrocyanide it 
gives a precipitate soluble in excess; it is not precipitated by potassium 
iodide. It differs from its isomer cinchonidin, by not precipitating with 
Rochelle salts. 

Cinchonin picrate melts 193-194° C. 

Cinchonin forms a well-defined sulphate, containing two molecules of 
water, which become anhydrous at 100° C. This salt is much more readily 
soluble in water than is quinin sulphate, the saturated solution being about 
2 per cent. The anhydrous salt is soluble in 60 parts of cold and in 22 
parts of boiling chloroform which distinguishes it from the sulphates of 
cinchonidin and quinin. 

Cinchonin hydrochloride contains two molecules of water and is readily 
soluble in water and alcohol, and somewhat in ether and chloroform. 

Cinchonin iodosulphate is used as an antiseptic and is sometimes sold 
under the name " Antiseptol." 

Ordinary commercial cinchonin contains considerable hydrocinchonin 
(cinchotin) often as much as 20 per cent, which renders the salts con- 
siderably more soluble than if chemically pure. Thus 1 part of pure cin- 
chonin sulphate is soluble in 72 parts of water at 12° C, while the ordinary 
commercial salt requires but 64 parts, 1 part of pure hydrocinchonin dis- 
solves in 37 parts of water. 

Cinchonin is readily converted into isomeric substances. On heating 
with acetic acid it gives rise to cinchotoxin, a highly poisonous base. 
Pure cinchotoxin, when heated, first softens and then melts at 58-59° C. 
It is readily soluble in alcohol, acetone, chloroform, and benzene. In hot 
petroleum spirit it is less soluble, and separates on cooling in oily drops, 
which crystallize after some time. In contact with water it gradually 
becomes fluid, and a small portion passes into solution. This solution 
is precipitated and rendered turbid by addition of an excess of alkali. 
Cinchotoxin yields a series of crystalline salts, and forms a hydrozone 



154 ALKALOIDAL DRUGS 

and several nitroso derivatives. The methyl derivative of cinchotoxin 
appears to be identical in all respects, chemical and physical — excepting 
some trifling differences in crystalline form, which require further investi- 
gation — with methyl-cinchonin. This similarity extends to their respec- 
tive derivatives. On the other hand, cinchotoxin itself is absolutely indis- 
tinguishable — again excepting very slight disparities in the form of the 
respective crystals — from cinchonicin. The study of this compound and 
its derivatives went a long way to establish the constitution of cinchonin. 

Cinchonin subjected to the action of sulphuric and hydrochloric acids 
under various conditions has yielded no less than 10 isomerides of the base, 
C19H22N2O, namely a and /3-isocinchonin, apoisocinchonin, apocinchonin, 
isoapocinchonin, diapocinchonin, dicinchonin, homocinchonin, pseudo- 
cinchonin, and cinchonicin. 

The experiments described show how easily one base may be converted 
into another, and that such a change may actually occur during the process 
of the extraction of a base from the plant, or during the purification. 

Cinchotenin 

Cinchotenin is obtained by the oxidation of cinchonin with potassium 
permanganate with the formation of formic acid. The following equation 
represents the change: 

C19H22N2O+O3 = C18H20N2O3+H • COOH 

The reaction is general for the cinchona alkaloids, and has been investi- 
gated in the cases of cinchonidin, quinin, and quinidin. • 

Cinchonidin 

Cinchonidin, the stereoisomer of cinchonin, accompanies quinin in 
all the cinchona barks, and in the extraction of the alkaloids it separates 
chiefly with quinidin. It is especially characteristic of the bark of C. 
succirubra. It crystallizes from alcohol in prisms melting 202-203°, 
very sightly soluble in water, somewhat soluble in ether and readily soluble 
in alcohol, chloroform, and amyl alcohol. Both the alkaloid and its salts 
are laevorotatory. 

Cinchonidin gives precipitates with all of the usual alkaloidal reagents 
and is distinguished from cinchonin by yielding insoluble compounds with 
potassium iodide and with Rochelle salt. The precipitate obtained with 
potassium chr ornate is much more soluble than that given with cinchonin. 
Its acid solution is not fluorescent and it gives no thalleoquin test. The 
" Herapathite " test described under quinin yields microscopic needles 
without metallic luster. The picrate darkens at 200° and melts at 208- 
209° with decomposition. 



ALKALOIDS DERIVED FROM QUINOLIN 155 

y Cinchonidin forms several well-defined salts, of which the sulphate is 
probably the one most universally met with in chemical work. The sul- 
phate crystallizes with varying amounts of water, depending on the con- 
centration and nature of the solvent; hot concentrated aqueous solutions 
yield a compound with three molecules of water, this being the salt official 
in the U. S. Pharmacopoeia. The crystals lose their water when heated 
to 100° C. The anhydrous sulphate is almost insoluble in absolute chloro- 
form, being similar to anhydrous quinin sulphate in this respect, and dif- 
fering markedly from the sulphates of cinchonin and quinidin which go 
into solution readily. 

In all of its reactions affecting its structure cinchonidin acts the same 
as cinchonin, most of their transformation and decomposition products 
being identical, 

Cinchotin 

This alkaloid, also called hydrocinchonin, contains two more hydrogen 
atoms than cinchonin and is found in crude cinchonin especially from the 
bark of Remejia purdieana. It may be isolated by treatment with perman- 
ganate which destroys the cinchonin more rapidly than the cinchotin is 
oxidized. It is dextrorotatory, melts at 286° (268° Mulliken), sparingly 
soluble in ether and forms addition products with hydrochloric and hydri- 
odic acids. It forms a compound with methyl iodide which separates 
from methyl alcohol in pale yellow crystals melting 234-235°. 

Cinchamidin 

This alkaloid, also called hydrocinchonidin, is isomeric with cinchotin, 
melts at 230°, is lsevorotatorj^ and resembles the latter in its general prop- 
erties. It dissolves with difficulty in ether and is almost insoluble in 
chloroform even when hot. Its solutions in dilute mineral acids are fluores- 
cent. 

Cinchonamin 

Cinchonamin, isomeric with cinchotin and cinchamin, is obtained from 
the bark of Remejia purdieana. It is dextrorotatory and melts 184-185° 
according to Pictet, though Chick gives 194°. It is readily soluble in 
the ordinary organic solvents except petroleum ether and is attacked by 
permanganate. It is seen commercially in the form of yellowish-white 
crystals and forms well-defined salts of which the nitrate is especially 
characteristic, being but slightly soluble in water and alcohol, and insolu- 
ble in dilute nitric acid. The compound is formed by dissolving the base 
in water containing a small quantity of hydrochloric acid, and adding a 
few drops of nitric acid. 



156 ALKALOIDAL DRUGS 

Cinchonamin does not give the thalleoquin test. With vanadium 
sulphuric acid (MandehVs reagent) it gives a bluish-violet color, changing 
to reddish violet and finally bluish green. With Froehde's reagent it 
gives a green tint turning yellowish green. 

Quinin 

This alkaloid is by far the most important of the cinchona group and 
is one of the most widely used of remedial agents. The analyst of drug 
products will frequently be called upon to identify it, to distinguish it 
from other bases of this group, and to determine it in mixtures with other 
alkaloids. It is not as easy of identification as strychnin, with which it is 
often mixed as its color reactions are less positive and those that it does 
possess are also common to other members of its own immediate family; 
but it is comparatively stable, and its solutions can be treated with reagents 
which will break up some of the more delicate alkaloids such as aconitin, 
atropin, and cocain, and by this means the latter if present may be removed, 
and quinin subsequently separated and purified. 

Quinin differs constitutionally from cinchonin and cinchonidin by pos- 
sessing an — OCH3 group and from our present state of knowledge its 
formula may be written as follows : 

H 

/ 

H2C CH2 CH — CHC=H2 

I ! I 

CH 2 COH CH 2 CH 2 

C C X N/ 

/\ /\ 
CH3OC C CH 

I II I 

HC C CH 

CH iN 

Commercial quinin is apt to retain traces of cinchonin, quinidin, hydro- 
quinin, and cinchonidin. It is laevorotatory while its stereoisomer quinidin 
is dextro. Quinin alkaloid, when precipitated out of solution, crystallizes 
as a white flaky or micro-crystalline powder; when obtained by evaporat- 
ing an ethereal solution, it is a colorless, hard, varnish-like mass, and if 
in large amount with a crystalline appearance in places. It is odorless 
and has an intensely bitter taste. When freshly crystallized it contains 
three molecules of water, two of which are lost on heating to 100° and the 
third at 125° C. The anhydrous alkaloid melts 171-172° C. while the 




ALKALOIDS DERIVED FROM QUINOLIN 157 

crystalline body with three H 2 fuses at 57°. The anhydrous body is 
slightly soluble in cold water but somewhat more readily when heated, 
it is fairly soluble in benzol and glycerin and readily in ether, and 
alcohol. The dry alkaloid is but slightly soluble in petroleum ether, but 
when freshly precipitated it is taken up by this solvent to a considerable 
extent the same as is strychnin. It is very slightly soluble in 20 per cent 
potassium hydroxide and about as soluble in dilute ammonia as it is in 
water. Its aqueous solution is alkaline to litmus. 

Quinin dissolves in sulphuric, acetic, and tartaric acids with a strong 
bluish fluorescence, discernible at great dilution and destroyed by the 
halogen acids. Quinidin, hydroquinin, hydroquinidin, and diquinicin 
give fluorescent solutions but quinamin, cinchonin, cinchonidin, cusconin, 
cuprein, and quinicin do not. This test will probably be the first indi- 
cation of the presence of quinin that the analyst will have in working 
with an unknown mixture, and will be noted early in the systematic scheme 
of separation. 

The thalleoquin test is a valuable confirmatory test for quinin. It 
is a test which is extremely delicate if carefully applied, but unless one is 
familiar with its vagaries it will often prove disappointing. Of all the 
well-known tests in alkaloidal chemistry this reaction will cause the analyst 
more uncertainty than any others. When there is a fair amount of the 
sample present it ought to be obtained without difficult}^, but if there is 
only a minute quantity available the result will more than likely be neg- 
ative. The directions in the Pharmacopoeia are as follows: 1 mil of an 
aqueous solution of the alkaloid 1-100 containing just sufficient sulphuric 
acid for solution is treated with 2 mils bromine water and 1 mil dilute 
ammonia water which will produce a green color. 

La Wall 1 has recently published a procedure by means of which he 
claims to be able to detect 1 : 200,000 of quinin by this test. According 
to the author 100 mils of a solution of the sulphate of the alkaloid to be 
tested at a dilution of 1 : 100,000 or 1 : 200,000 are poured into a Nessler 
tube, 5-10 drops of potassium bromate solution (0.5 gram potassium bro- 
mate, 10 mils hydrobromic acid 10 per cent and 90 mils water) added, 
the contents well mixed and then treated with 10 drops stronger ammonia 
water, which will produce a green tint in presence of quinin or other cin- 
chona alkaloid giving the thalleoquin test. A modification of the thal- 
leoquin test known as the erythroquin test and valuable as confirmatory 
evidence, consists in following the bromin water with a few drops of 
potassium ferro- or ferricyanide, and subsequently with ammonia, when 
a red coloration is produced instead of the green ; on shaking with chloro- 
form the coloring matter will dissolve and appears to better advantage 
especially in very dilute solutions. 

1 Amer. J. Pharm., 1912, 84, 484. 



158 ALKALOIDAL DRUGS 

Buchbinder's directions for conducting this test are as follows: Have 
ready a test-tube (No. 1) containing 1 mil of chloroform and 3 mils of a 
saturated solution of potassium ferrocyanide. In another test-tube (No. 
2) pour 5 drops of bromine water. Working as rapidly as possible, add 
to test-tube No. 2, 1 or 2 mils of the solution to be tested; immediately 
pour the contents of test-tube No. 2 into test-tube No. 1 and shake 
thoroughly. Add a little concentrated ammonia and shake again. A pink 
to red coloration will appear in the chloroform layer if quinin is present. 
If a precipitate forms on adding the solution to the bromin water, the 
test may possibly fail. In that case, repeat with a more dilute solution. 
The important point to be observed is' the immediate removal of free bro- 
min by the introduction of the ferrocyanide solution. Buchbinder claims 
that the test is sensitive to 0.02 mg. of quinin. 

The thalleoquin test is also given by quinidin, cuprein, hydroquinin, 
hydroquinidin, and diquinicin, but not by quinamin, cinchonin, nor cin- 
chonidin. Pilocarpin, cocain, atropin, codein, and strychnin do not inter- 
fere with the reaction but morphin does, as well as antipyrin and caffein, 
in certain proportions. Caffein can of course be removed by shaking it 
out of an acid solution and morphin may be eliminated if the quinin is 
separated by ether, in fact the quinin should be as pure as possible before 
applying this test. 

When an alcoholic solution of iodin is added to an acid solution of 
quinin sulphate, a precipitate of the black or bronze iridescent iodo-sulp- 
phate is produced known as Herapathite. The directions for this test 
in the U. S. Pharmacopoeia are as follows: 0.7 gram of quinin are dis- 
solved in 15 mils of acetic acid, 6 mils alcohol and 0.5 mil sulphuric acid 
added and the solution heated to boiling, 7 mils of saturated solution of 
iodine in alcohol are added and the mixture allowed to cool when the 
Herapathite will gradually separate. It may be filtered off, washed, and 
recrystallized from hot alcohol. Quinidin, cinchonin, and cinchonidin 
also gives the iodosulphate, but that of quinin is much more insoluble in 
alcohol, and is soluble in water with difficulty. 

0.2 gram of quinin dissolved in 1 mil of dilute sulphuric acid, diluted 
with water to 20 mils, the acid neutralized with ammonia, treated with 1 
drop of hydrogen peroxide and 1 drop of copper sulphate 10 per cent and 
boiled, yields an intense red color which slowly changes to blue and finally 
to green. Quinidin also gives tins test. 

0.2 gram of quinin dissolved in 2 mils of concentrated sulphuric acid 
and treated with 0.5 mil hydrogen peroxide gives a deep yellow color 
gradually fading to light yellow which persists for a considerable time. 

Quinin gives a well-defined precipitate with potassium chromate sepa- 
rating from a solution of 1-200; quinidin is also precipitated by this 
reagent as a fairly insoluble precipitate, but the chromates of cinchonin 



ALKALOIDS DERIVED FROM QUINOLIN 159 

and cinchonidin are much more soluble. The use of this compound has 
been proposed for the quantitative estimation of quinin, but its value is 
questionable and its use even for qualitatively distinguishing quinin from 
the other bases is not satisfactory. 

Potassium iodide does not give a precipitate with quinin. This will 
distinguish quinin from quinidin and cinchonidin but not from cinchonin. 

Potassium ferrocyanide gives a reddish-brown color, but no precipitate 
with dilute solutions of quinin; with quinidin a white flocculent precipi- 
tate is formed; with cinchonin and cinchonidin a white precipitate is 
thrown down soluble in excess. 

Mercuric chloride does not precipitate dilute solutions of quinin until 
a considerable excess has been added while quidinin, cinchonin, and cin- 
chonidin give immediate precipitates. 

The ordinary alkaloidal reagents, Mayer's reagent, Wagner's reagent, 
potassium bismuthic iodide, phosphomolybdic and phosphotungstic acids, 
gold and platinic chlorides, and picric acid all give precipitates with quinin. 
With phosphotungstic acid a pink fluorescence is also noticeable. 

Quinin picrate melts 125-126° C. This salt should always be made 
and identified when the identity of quinin is in question. 

Salts of Quinin 

Quinin forms a number of crystallizable salts, several of which are 
official, and these and many others are used medicinally. There is also 
a series of acid salts, usually much more soluble than the normal com- 
pounds, and on this account much preferred for certain purposes. 

The most important salt is the sulphate, (C2oH 2 402N 2 )2H2S04 • +7H2O 
which is perhaps the most extensive^ employed alkaloidal salt in the 
realm of medicine, rivaling morphin sulphate-, cocain hydrochloride and 
strychnin sulphate, and possibly exceeded by the two former only on 
account of their vast illegitimate use. The commercial salt is seldom free 
from small quantities of allied bases. Cinchonidin is sometimes added 
in amounts of about 1 per cent in order to produce the fluffy appearance 
so much desired. The standard allows for minute quantities of these alka- 
loids and tests are included in the pharmacopoeia for their detection if 
present in excessive amounts and as the drug analyst may be called upon 
to pass upon the purity of this body some detailed points about the vari- 
ous tests will be of interest. 

This salt occurs in white lustrous or shining, fragile, needle-like crys- 
tals, very compressible and becoming dark if exposed continually to the 
light. When chemically pure the appearance is modified, the needles 
being less bulky and the salt is known as the " heavy sulphate." It is but 
sparingly soluble in cold water, requiring over 700 parts of the solvent 
to effect solution ; in hot water it dissolves much more readily and on cool- 



160 ALKALOIDAL DRUGS 

ing the crystals separate. In alcohol its solubility is about 1-65 cold and 
1-3 boiling, and it dissolves with ease in a mixture of chloroform — abso- 
lute alcohol 2-1. It is sparingly soluble in chloroform and practically 
insoluble in absolute ether and petroleum ether. It is always slightly 
alkaline to litmus even when crystallized out of acid solutions. 

The commercial salt always contains a little cinchonidin and hydro- 
quinin and may also contain cinchonin, quinidin, and amorphous bases, 
and to detect the presence of undue quantities of these other alkaloids 
various tests have been proposed. The test which has been most exten- 
sively adopted for this purpose in the different pharmacopoeias is the so- 
called ammonia test originally proposed by Kerner. It depends upon the 
fact that, while quinin sulphate is less soluble in water than the sulphates 
of the accompanying bases, quinin itself when freshly precipitated by 
ammonia is much more soluble in the latter than the other free bases. 
The procedure consists in treating 5 mils of an aqueous solution of the 
salt, saturated at 15° C, with 10 per cent ammonia water and noting the 
amount which will yield a clear solution. The limit varies, thus our own 
standard and the Italian is 7 mils, the French 5, the Netherlands 4.5 and 
the German 4. The results are only empirical as it is difficult to dissolve 
out cinchonidin sulphate from crystals of quinin sulphate, and cinchonidin 
sulphate forms a double salt with quinin sulphate in crystallizing. Tutin ] 
has made an exhaustive study of this test working from the pure salt 
which he prepared by repeated crystallization and manipulation of the 
alkaloid through the d-camphorsulphonate and the d-bromcamphorsul- 
phonate. He shows that the minimum amount of 10 per cent ammonia 
which will yield a clear solution at 15° C, with 5 mils of a solution of pure 
quinin sulphate saturated at 15° C. is 4.4 mils. He states that it is impos- 
sible to meet the German standard and that the French and Netherlands 
standards are more stringent than is desirable. It is evident then that 
our standard is the fairest where the manufacturer is concerned, and other 
things being equal, is safe for the consumer. Tutin belives that a mini- 
mum of 6 mils is a reasonable requirement, and leans towards the manipu- 
lation of the French Pharmacopoeia, by which 1 gram of the salt is dis- 
solved by boiling with 30 mils of water, cooled to 15° C, allowed to stand 
| hour and then 5 mils of the clear liquid treated with the ammonia. Tutin 
proves also that the basicity of the salt has the same effect as an impurity, 
and hence commercial salts which frequently contain a little free alkaloid, 
may appear to be far less pure than is actually the case. Finally alkaline 
sulphates if present will decrease the solubility of the quinin sulphate to 
such an extent that an impure product may appear purer than one which 
is strictly pure. The presence of inorganic salts may be ascertained by 
evaporating the aqueous solution to dryness and examining the residue for 
1 Amer. J. Pharm., 1912, 84, 484. 



ALKALOIDS DERIVED FROM QUINOLIN 161 

alkali bases and ammonia. Tutin concludes that this test is valueless as 
a means of ascertaining the purity of any salt of quinin, other than the 
normal sulphate, but in the case of this salt it is the only means of detect- 
ing hydroquinin without actually isolating that alkaloid. 

The next scheme to be considered in the examination for impurities 
will be the test for the separate alkaloids as elaborated in the British 
Pharmacopoeia. 

Test for Cinchonidin and Cinchonin. — Dissolve 4 grams of the quinin 
sulphate in 120 mils of boiling water. Cool the solution slowly to 50° 
with frequent stirring. Separate, by filtration, the purified quinin sul- 
phate which has crystallized out. Concentrate the nitrate by evapor- 
ation until it is reduced to 10 mils or less; transfer to a small stoppered 
flask and when cool, shake with 10 mils ether and half that amount of 
solution of ammonia. Set aside in a cool place for not less than twenty- 
four hours. Collect the crystals which consist of cinchonidin and cin- 
chonin combined with quinin on a tared filter, wash with a little ether, 
dry at 100° and weigh. Those should not amount to more than 0.12 gram. 

If this test is performed with ordinary ether an admixture of 7 per cent 
cinchonidin will escape detection, but if absolute ether is used 3 per cent 
of this alkaloid can be detected. 

Test for Quinidin. — Dissolve 1 gram of the quinin sulphate in 30 mils 
of boiling water, cool, and filter. To the solution add solution of potas- 
sium iodide and a little 90 per cent alcohol to prevent the precipitation 
of amorphous hydriodides. Collect any separated quinidin hydriodide 
wash with a little water, dry, and weigh. The weight represents about 
an equal weight of crystallized quinidin sulphate. 

Test for Cuprein. — Shake the recrystallized quinin sulphate obtained 
in testing the original quinin sulphate for cinchonidin and cinchonin with 
25 mils of ether and 6 mils solution of ammonia, and to this ethereal solu- 
tion separated, add the ethereal liquid and washings also obtained in 
testing the original sulphate for the two alkaloids just mentioned. Shake 
this ethereal liquid with 6 mils of 10 per cent sodium hydroxide, adding 
water if any solid matter should separate. Remove the ethereal solu- 
tion, wash the aqueous solution with more ether and remove the ethereal 
washings. Add diluted sulphuric to the aqueous liquid heated to boil- 
ing until exactly neutral. When cold collect any crystallized sulphate 
of cuprein on a tared filter, dry and wash 

Test for Cinchonin and Amorphous Alkaloids. — Dissolve 1 gram of 
quinin sulphate in 30 mils of boiling water. Add 1 gram sodium potas- 
sium tartrate. Allow to cool with frequent shaking and filter. The 
solution when evaporated to small bulk should give little or no precipi- 
tate with solution of ammonia. 

Another type of test useful for detecting the presence of cinchonin 



162 ALKALOIDAL DRUGS 

and quinidin has been proposed by Hesse and depends on the difference 
in their solubliities in chloroform. The quinin sulphate is dried at 100° 
C. and 1 gram agitated with 15 mils of alcohol-free chloroform, the solvent 
is filtered and 10 mils evaporated; which should not leave a residue of 
more than .035 gram. If the residue is crystalline and less than the above 
weight it may be tested for cinchonin and quinidin by warming it with 
5 mils of water, adding 0.5 gram of sodium potassium tartrate, cooling, 
filtering, and treating the filtrate with an equal volume of ammonia water. 
If quinidin or cinchonin are present a precipitate will be formed. Cin- 
chonidin sulphate if present will swell up into bulky needles when treated 
with chlorofrom, but it does not dissolve, and the solvent may be separ- 
rated by pressure. 

If a solution of quinin sulphate is treated with an excess of potassium 
chromate and allowed to stand several hours, the quinin is almost entirely 
precipitated. On filtering and adding sodium hydroxide to the filtrate 
the solution will remain clear if the quinin is pure, but will become tur- 
bid in the presence of 1-2 per cent of allied alkaloids. 

The examination of quinin sulphate for amorphous alkaloids has been 
studied by DeVrij, who recommends adding ammonia to an acid solu- 
tion of the salt and then shaking out with ether in order to obtain the 
free alkaloids. After evaporating the solvent the residue is treated with 
N/10 oxalic acid in sufficient amount to convert the alkaloids into neu- 
tral oxalates, the liquid is evaporated over the steam-bath and the resi- 
due dried. The neutral oxalates are then dissolved in chloroform and 
the solution filtered and treated with a few drops of water when crystals 
of quinin oxalate will appear in the solvent. In the case of a pure sample 
the water will remain clear and uncolored, but if amorphous alkaloid 
is present the water will be colored yellow. 

A number of methods have been proposed for determining the purity 
of quinin sulphate by reference to its rotatory power, but there are so 
many conditions which impair the accuracy of any observations of this 
property that the writer has decided to omit them. 

The determination of the amount of alkaloid in a sample of quinin 
sulphate is readily effected by dissolving a weighed quantity in water 
slightly acidulated with sulphuric acid, adding a slight excess of ammonia 
and shaking out three times with ether. The combined ethereal solu- 
tions are washed with water and the solvent solution filtered into a tared 
dish, the ether evaporated and the residue brought to a constant weight 
at 100° C. If desired the gravimetric estimation may be checked titri- 
metrically and for this purpose attention is called to Elvove's procedure ;* 
about 0.2 gram of the alkaloidal residue is dissolved in an excess of dilute 
hydrochloric acid 4 per cent, the liquid completely evaporated, the sur- 
i Hyg. Lab. U. S. P. H. & M. H. Service Bui. 54 



ALKALOIDS DERIVED FROM QUIXOLIN 163 

face film being broken up from time to time with a glass rod, the residue 
allowed to remain in the water-bath for three hours, then dissolved in 
10-20 mils of water, 3 drops phenolphthalein added, and titrated with 
standard sodium hydroxide until the solution develops a faint pink color. 
At this point one more drop of the indicator is added and if the solution 
at once assumes a very deep pink color, standard acid is added until the 
color remaining is only light pink, the alkali equivalent of the acid just 
added being deducted from the total alkali added first. Two molecules 
of sodium rrydroxide are equivalent to one molecule of quinin. The 
method is applicable to quinidin, cinchonin, and cinchonidin. 

Iron and Quinin Citrate 

The Pharmacopoeia formerly recognized two products under this title, 
one readily soluble and the other slowly soluble, and both containing, 
11.5 per cent quinin and 13.5 per cent metallic iron. The ninth revision, 
however, has deleted the less readily soluble compound. These bodies 
are really mixtures of iron citrate and quinin citrate containing more or 
less ammonium citrate. The more readily soluble of the two occurs in 
thin transparent scales of a greenish-golden-yellow color and the other 
in reddish-brown scales. They are both partially soluble in alcohol. 
The iron does not respond to the ordinary qualitative tests, but if the 
quinin is precipitated by ammonia and the filtrate acidulated with hydro- 
chloric acid the Prussian blue reaction will be given with potassium fer- 
rocyanide. The official assay's for quinin and iron are as follows: 

Dissolve about 1 gram of Iron and Quinin Citrate, accurately weighed, 
in 20 mils of distilled water in a separator, add 5 mils of ammonia water 
and 10 mils of chloroform, and shake the separator for one minute. Allow 
the liquids to separate, draw off the chloroform layer through a small 
filter moistened with chloroform, into a tared dish, and shake the resid- 
uary liquid a second and a third time with portions of 10 mils each of 
chloroform, passing the chloroform through the filter each time and finally 
washing the filter with 5 mils of chlorofrom. Evaporate the combined 
chloroform solutions, redissolve the residue in 3 mils of alcohol, again 
evaporate and then dry the residue to constant weight at 100 c C. This 
residue corresponds to not less than 11.5 per cent of the amount of Iron 
and Quinin Citrate taken for the assay and conforms to the identity tests 
under Quinin. 

Assay for Iron. — Heat the aqueous liquid, from which the quinin has 
been removed in the manner just described, on a water-bath, until the 
odors of chloroform and of ammonia have disappeared, allow to cool, and 
dilute with distilled water to a volume of 25 mils. Transfer the liquid 
to a glass-stoppered bottle, add 15 mils of hydrochloric acid and 3 grams 
of potassium iodide, and, after securely closing the bottle, allow the mix- 



164 



ALKALOIDAL DRUGS 



ture to stand for thirty minutes at 40° C. Then cool and titrate with 
sodium thiosulphate, using starch as indicator. It shows not less than 
13 per cent of Fe. 

Each mil of N/10 sodium thiosulphate used corresponds to 
0.005584 gram of Fe. Each gram of Iron and Quinin Citrate corresponds 
to not less than 23.3 mils of N/10 sodium thiosulphate. 

Quinin and Urea Hydrochloride 

C 2 oH2 4 N 2 02 • HCI+CH4N2O • HC1+5H 2 0. 

This salt in aqueous solution is used to a limited extent for hypodermic 
injections and exerts an anesthetic action similar to that of cocain. It 
occurs in white crystals which are very soluble in water. 

QUINIDIN 

Quinidin is the stereoisomer of quinin. It rotates the plane of polarized 
light to the right, melts 168-171.5°, the latter figure being obtained with 
the anhydrous alkaloid. It crystallizes from alcohol and ether with 
water of crystallization and may be rendered anhydrous by heating to 
120°. It is readily soluble in ether and alcohol, somewhat soluble in 
chloroform and benzol, and slightly soluble in water, 

It resembles quinin in its reactions, but differs from quinin in giving 
a very sparingly soluble precipitate with potassium iodide. It also gives 
a permanent bulky precipitate when its solution is treated with chlorin 
water, potassium ferricyanide, and ammonia. Quinidin picrate melts 
137-138° C. Quinidin is marketed in the form of the sulphate which 
contains two molecules of water. This salt is soluble in 20 parts of chloro- 
form. It may be examined for other alkaloids by dissolving 0.5 gram 
in 10 mils water and adding .5 gram neutral potassium iodide, stirring, 
cooling, and filtering after half an hour from the precipitated hydriodide; 
the filtrate is then treated with 1-2 drops of ammonia water and if a pre- 
cipitate is thrown down the presence of other alkaloids is indicated. 

The commercial salt usually contains traces of hydroquinin and hydro- 
quinidin. 

0.2 gram quinidin treated with 2 mils concentrated sulphuric acid and 
0.5 mil hydrogen peroxide gives a yellow color turning to a deep orange 
and gradually fading to colorless. 



HYDROQUININ AND HYDRO QUINIDIN 

The two alkaloids differ constitutionally from quinin and quinidin 
by containing two more hydrogen atoms, and occur with them in the com- 
mercial salts. They are stable to permanganate and may be separated 



ALKALOIDS DERIVED FROM QUINOLIN 165 

by treating the mixture with this reagent which destroys quinin and quin- 
idin. Hydroquinin is laevorotatory and in the anhydrous state melts 
172°. Hydroquinidin is dextrorotatory and melts 166-167°. They both 
give fluorescent solutions with acids and respond to the thalleoquin tests. 

QUINAMIN AND CONQUINAMIN 

These two isomeric bodies occur in a number of different species of 
Cinchona and are probably present in small amounts in commercial Cin- 
chona alkaloids. They are both dextro, the latter more strongly, and 
are soluble in the ordinary organic solvents. Quinamin melts 172° and 
conquinamin 121-123°. Quinamin hydrochloride reduces gold chloride 
solution. 

Mulliken describes the following reaction of quinamin. If a solu- 
tion of the salt strongly acidified with sulphuric acid is smeared over white 
paper and held over a watch glass containing sulphuric acid and potas- 
sium chlorate, the lines become olive green in color and on exposure to 
air turn blue. 

CUPREIN 

Cuprein occurs in the bark of Remijia pedunculata and in other species 
of Remijia. It differs from most of the other alkaloids of this family in 
uniting with alkalies and some of the less basic elements to form definite 
soluble salts, this property being due to the presence in its molecule of 
an hydroxyl group having a phenolic character. Its alcoholic solution 
gives a reddish-brown color with ferric chloride. It is sparingly soluble 
in ether and chloroform, but when precipitated from its acid solution by 
ammonia can be removed from the mixture by these solvents. Fixed 
alkalies dissolve the precipitated alkaloid, and ether cannot remove it 
from this solution. 

Cuprein melts 198° after drying at 125° C, is laevorotatory, gives the 
thalleoquin test, but its acid solutions do not fluoresce. It forms stable 
crystalline compounds with the cinchona bases, one of which, homoquinin, 
has been carefully studied. The latter is obtained when molecular pro- 
portions of quinin and cuprein are dissolved in dilute acid, precipitated 
with ammonia and shaken out with ether, which leaves the double body 
on evaporation. Its salts differ from those of either of its two components. 
Homoquinin may be separated into its constituents by treating an acid 
solution with excess of fixed alkali and shaking out the quinin with ether, 
the cuprein remaining in solution. 

Cuprein forms two classes of salts the normal being but slightly sol- 
uble in water. 

The relationship of cuprein to quinin is the same as that of phenol to 
its methyl ether. The transformation of cuprein into quinin is effected 



/ 



166 ALKALOIDAL DRUGS 

by treating a solution of cuprein in methyl alcohol with sodium and then 
with methyl iodide, the temperature, starting from zero, being gradually 
raised during several hours. Under these conditions quinin itself is not 
formed, but quinin mono- and dimethyl iodides. When operating in a 
closed vessel with an excess of methyl iodides only the latter body is 
produced. Methyl-cuprein-dimethyl iodide agrees in all its properties 
with quinin-dimethyl iodide, as is shown by the following figures: 





Quinin dimethyl iodide 




Synthetical 


Natural 


Melting-point (with partial decomposition) 


167-168° C. 

—150.8 

41.34 


167-168° C. 


Rotatory (a) D 

Percentage of iodine 


—151.6 
41.77 







If the methyl iodide be replaced by methyl chloride, free quinin is 
formed. A mixture of one molecule of cuprein, one atom of sodium and 
one molecule of methyl chloride dissolved in methyl alcohol, is heated to 
100° C. in a closed tube. The product of the reaction is evaporated to 
dryness, washed with a dilute soda solution in order to remove any unal- 
tered cuprein, and finally extracted after conversion into sulphate of quinin, 
the product resembles the natural article in all respects, 

ALKALOIDS OF THE CUSCONIN CLASS 

This group is found in Cusco bark and probably in other species of 
Remiiia. Chick gives them all the same formula, C22H26N2O4, but Pictet 
gives one more carbon atom to aricin, cusconin, and concusconin. Pictet's 
summary of their characteristics is as follows: 

Chairamin occurs in needles or prisms, which in the hydrous con- 
dition melt at 140°, in the anhydrous at 233°. It is dextrorotatory. 

Chairamidin is amorphous and dextrorotatory and in the anhydrous 
condition melts at 126-128°. 

Conchairamin is a very weak base, dextrorotatory, melting in the 
anhydrous condition at 120°. 

Conchairamidin occurs in laevorotatory needles melting in the anhy- 
drous condition at 114-115°. 

Aricin crystallizes from alcohol in prisms melting at 188°. It is lsevo- 
rotatory in neutral solution, inactive in hydrochloric acid. 

Cusconin crystallizes in prisms melting at 110° and is laevorotatory. 

Concusconin is a dextro base melting at 206-208°. 

Cuscamin and cuscamidin have been mentioned, but a description of 
their properties is lacking. 



ALKALOIDS DERIVED FROM QUINOLIN 167 

QUINICIN AND CINCHONICIN 

Quinicin and cinchonicin are amorphous bases resulting respectively 
when quinin and cinchonin are heated under certain conditions. Quinicin 
is dextrorotatory, gives the thalleoquin reaction, is readily soluble in alco- 
hol and ether, and forms a number of crystalline salts. It is not pre- 
cipitated by Rochelle salt, but gives insoluble precipitate with potassium 
thiocyanate, and a white precipitate with hypochlorites. Cinchonicin 
resembles the above base in most of its properties but does not give the 
.thalleoquin test. Quinicin melts 60° and cinchonicin 58-59° C. 

DIQUINICIN AND DICINCHONICIN 

These two bases, also amorphous, make up the greater part of quin- 
oidin. The former may be considered an anhydride of quinin or quinidin 
and the latter as a double molecule of cinchonin or cinchonidin, though 
this has been disputed. Diquinicin gives the thalleoquin test and its acid 
solutions are fluorescent, dicinchonicin does not answer these tests. 

DeVrij has worked with the amorphous bases and distinguishes them 
by the behavior of their neutral oxalates rendered anhydrous at 100° C. 
Quinicin oxalate is almost insoluble in cold chloroform, and though it dis- 
solves in the hot liquid it is deposited again on cooling. Cinchonicin 
oxalate is readily soluble in cold chloroform and on adding a few drops 
of water the solution solidifies. The oxalates of the natural amorphous 
bases dissolve easily in chloroform and the solution does not solidify on 
adding water. 

Quinoidin is the name given to a brownish-black resinous-appearing 
mixture of amorphous cinchona alkaloids which has a somewhat limited 
use in manufacturing pharmacy. The alkaloids composing it are those 
left in solution after the crystalline alkaloids have been removed. It 
is soluble in dilute acids, alcohol, and chloroform. Several of its salts, 
including the borate, citrate, hydrochloride, sulphate, and tannate are 
commercial articles. 

EXAMINATION OF CINCHONA BASES FOR IDENTIFICATION 

Though these alkaloids are of common occurrence in medicinal prep- 
arations, the individuals are among the most unsatisfactory of chem- 
ical bodies to identify. They follow one another closely in their solubil- 
ities, and it is next to impossible to effect a complete isolation of any one 
by ordinary analytical reactions. We state that cinchonin and cinchon- 
idin do not give fluorescent solutions with acids, and yet there is probably 
no commercial salt of these alkaloids which will not give a fluorescent, 
solution. It is well known that these same alkaloids do not give the 



168 ALKALOIDAL DRUGS 

thalleoquin test, but unless one is fortunate in his manipulation, he will 
often fail to get this reaction with quinin and quinidin, and when work- 
ing with small quantities perhaps be unable to obtain it at all. Any 
alkaloidal residue obtained from a preparation containing an extract of 
cinchona will give a fluorescent solution with dilute sulphuric acid, and 
will more than likely contain quinin, cinchonin, cinchonidin, and perhaps 
quinidin in varying proportions. In fact in many instances the worker 
can report the presence of cinchona alkaloids, and that is about as far 
as he can go. Any method of separation of the main alkaloids requires 
a sample which, in quantity, is almost prohibitive unless it happens to 
be a " pure " salt, and is of no value for the relatively small residues 
which one ordinarily obtains. 

If the residue in question is transparent, colorless, and hard like a var- 
nish with perhaps here and there the appearance of a crystalline form, 
it probably consists entirely of quinin. A good thalleoquin test will indi- 
cate quinin or quinidin. If a neutral solution gives a copious precipitate 
with potassium iodide and the filtrate yields but a small quantity of alka- 
loid after treatment with alkali and shaking out with ether, the substance 
is chiefly quinidin. Cinchonidin will give a curdy precipitate under similar 
conditions while that obtained with quinidin will be granular if the orig- 
inal material is pure, but of course cinchonidin does not respond to the 
thalleoquin test. 

Quinin and quinidin when dissolved in concentrated sulphuric acid 
and treated with 0.5 mil hydrogen peroxide give deep-yellow solutions, 
becoming orange in the case of quinidin and then gradually fading to 
yellow, the quinin solution holding its color over an extended period. 
When cinchonin or cinchonidin are treated under like conditions they 
give light-yellow solutions which soon fade. 

The iodosulphates of the cinchona base differ considerably in their 
solubilities and appearances; quinin iodosulphate is black and iridescent 
and but slightly soluble in water or dilute alcohol, quinidin iodosulphate 
is reddish brown and much more soluble, so that it often takes consider- 
able time to precipitate; the cinchonidin compound is slightly less sol- 
uble and the cinchonin compound more soluble than that of quinidin. 

Potassium ferrocyanide gives a white flocculent precipitate with quini- 
din, a reddish-brown color with quinin, and a white precipitate soluble 
in excess with cinchonin and cinchonidin. 

The directions of rotation of polarized light is to the right with quini- 
din and cinchonidin and to the left with quinin and cinchonin, but this 
property is of little value as a means of identification unless the sample 
is comparatively large. 

It will be noted from the above paragraphs that the tests for cinchonin 
and cinchonidin are much less positive than those for quinin and quinidin. 



ALKALOIDS DERIVED FROM QUINOLIN 169 

If one has sufficient residue it should be carefully purified, heated to 
125°, allowed to stand in a desiccator and its melting-point taken. Quinin 
melts at 171-172°, quinidin 168-171.5°, cinchonin 250-265°, and cinchon- 
idin 202-203°. In all cases the picrate should be prepared and its melt- 
ing-point determined. 

With the above notes in mind the examination of an alkaloidal resi- 
due, suspected of being composed of one or more members of the Cin- 
chona group, may take the following course. If the sample under con- 
sideration contains an extract of any of the Cinchonas or Remijias, a solu- 
tion of the alkaloids in dilute sulphuric acid will almost invariably have 
a bluish fluorescence and the alkaloidal residue obtained therefrom will 
contain several different alkaloids in varying proportions. If there is 
sufficient quantity for preliminary tests, small portions of the residue 
should be treated separately with bichromate and sulphuric acid, form- 
aldehyde-sulphuric acid, nitric acid and evaporated and the residue treated 
with a few drops of alcoholic potash in order to insure the absence of some 
of the main groups of alkaloids. The next step should be the determi- 
nation of the melting-point as described in the preceding paragraph. Then 
the test with sulphuric acid and peroxide should be tried, followed by the 
thalleoquin, herapathite, the potassium iodide and the ferrocyanide tests 
and the melting-point of the picrate determined and with the data obtained 
the identity of the individual can be very closely established. The vari- 
ous other properties of the individual can then be tested and checked 
with the descriptive data. 

In order to effect a separation of the main alkaloids when they occur 
together, Chick, in the new edition of Allen, describes DeVrij's scheme, 
which was also used in the former edition. It will be described here in 
brief, as it is a valuable method, not only for separating the alkaloids 
themselves, but as an aid in establishing the identity of an individual. 
The sample, which should not amount to less than 2 grams, in a state of 
fine division, is treated in a small Erlenmeyer flask with ten times its 
weight of absolute ether and well shaken, the flask stoppered and allowed 
to stand for twelve hours. It is then filtered into a tared dish, and the 
residue washed with a small quantity of ether, and the filtrate evaporated 
to dryness and weighed. This residue consists of quinin, quinamin, amor- 
phous alkaloids, and traces of quinidin and cinchonidin, the portion 
insoluble in ether being composed of cinchonin, cinchonidin, and quinidin. 
The residue containing the quinin is then dissolved in 10 parts of 50 per 
cent alcohol acidified with 1/20 of sulphuric acid and treated with an 
alcoholic solution of iodin as long as a precipitate is obtained, avoiding 
an excess of the reagent. If much quinin is present a black precipitate 
of herapathite is immediately produced but if the quantity is small some 
time is required for its appearance, and in this case only a small quantity 



170 



ALKALOIDAL DRUGS 



of iodin should be added and the solution well stirred and allowed to 
stand twelve hours. The precipitate is then filtered off, washed with 
strong alcohol, decomposed with sulphurous acid and the quinin liberated 
with ammonia and extracted with ether. The alcoholic filtrate and wash- 
ings are then rendered colorless with sulphurous acid and carefully neu- 
tralized with sodium hydroxide, the alcohol evaporated, the residue made 
alkaline and shaken out with chloroform. After evaporating the solvent 
the amorphous alkaloids will dissolve in a limited amount of ether, leav- 
ing most of the quinidin and cinchonidin behind. 

The bases which were insoluble in ether are then dissolved in dilute 
sulphuric acid, the solution exactly neutralized with sodium hydroxide, 
an excess of saturated solution of Rochelle salt added, cooled to 15° C. 
and allowed to stand for one hour. If cinchonidin is present, crystalline 
streaks of the tartrate form, the solution is filtered off and washed with 
5 per cent solution of Rochelle salt. The filtrate is concentrated to its 
original volume, a drop of acetic acid is added and an excess of a saturated 
solution of potassium iodide. The mixture i& allowed to stand for two 
hours at 15° C. with frequent stirring, and if quinidin is present, a pre- 
cipitate of the hydriodide is formed which is filtered, washed with cold 
water, and the alkaloid recovered by treatment with ammonia and agi- 
tation with chloroform. The filtrate and washings from the hydriodide 
precipitate is then made alkaline with sodium hydroxide and the cin- 
chonin extracted with chloroform. 

As illustrative of the peculiarities of this group it may happen that 
when working with the mixed alkaloids an ethereal solution will yield a 
quantity of a molecular combination, for instance, of quinin and quinidin. 
When these crystals are dissolved in sufficient sulphuric acid to form the 
neutral salt, quinin sulphate will crystallize and the mother liquor will 
contain quinidin sulphate. The crystalline compound above mentioned 
will be but slightly soluble in ether, though it is more soluble in ethereal 
solution of quinin and such a solution frequently exhibits supersaturation, 
remaining clear for some time and then suddenly giving a cloud of crys- 
tals. 

Quantitative Estimation. — The quantitative estimation of the indi- 
viduals of this group presents little difficulty; the alkaloids are compar- 
atively stable, they will stand considerable manipulation, and it is only 
when they occur together with some strong base like strychnin that their 
separation becomes involved. 

In order to determine quinin or the allied bases in tablet triturates 
or plain compressed tablets of the sulphate or bisulphate, the sample 
amounting to 10 or 25 tablets should be introduced into a 250-mil sepa- 
rator of the Squibb type, moistened with water, shaken until disinte- 
grated and then made alkaline with ammonia. About 25 mils of ether 



ALKALOIDS DERIVED FROM QUINOLIN 



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172 ALKALOIDAL DRUGS 

are added and the separator shaken, the aqueous mixture drawn off into 
another separator and the operation repeated twice, which is sufficient 
to remove all of the alkaloid. The ethereal solution may then be con- 
centrated to about 50 mils and shaken out three times with 15 mil portions 
of dilute sulphuric acid, the quinin liberated from the acid with ammonia 
and shaken out three times with 25-mil portions of ether, the combined 
ether shake-outs washed with water, filtered into a tared dish, evaporated, 
and the residue weighed. This residue is sufficiently pure to render a 
titration unnecessary. 

With pills and coated tablets the disintegration will probably be slower, 
but the general plan described above should be followed, though to avoid 
emulsification the first extraction may be accomplished with Prolius mix- 
ture. If Prolius is used the solvent should be evaporated and the residue 
dissolved in dilute acid as the removal of an alkaloid from Prolius solu- 
tion by acid is unsatisfactory. 

Quinin sulphate in capsules is usually mixed with milk sugar. The 
contents of the capsules should be poured into a separator and treated as 
under tablet triturates. 

When a liquid preparation is under examination and it has been found 
that cinchona bases are the only alkaloidal constituents, a quantity amount- 
ing to 25 or 50 mils should be washed into a separator, treated with excess 
of ammonia and shaken out with ether or Prolius, depending on its 
behavior, and the alkaloids purified in the usual way. Some liquid prepa- 
ations contain but small quantities of the alkaloids, and for products of 
this type, which include various bitters and quinin whiskies, a generous 
sample amounting from 100-500 mils should be concentrated to about 
50 mils, then made alkaline and the determination continued. 

Where quinin has been identified in tablets which also contain resin- 
ous drugs, the sample should be thoroughly ground up in a mortar and 
extracted four or five times with alcohol, the alcoholic solution evaporated 
in the presence of a little acidified water, and when the alcohol has been 
driven off sufficiently to precipitate the resins, the liquid is filtered into a 
separator and the dish and filter washed three times with 15-mil portions 
of hot dilute acid. From this point the determination may follow the 
regular scheme. 

Quinin will often be found in combination with the belladonna alka- 
loids and with strychnin and less often with the opium and ipecac alka- 
loids. The manipulation of a product in which the belladonna alkaloids 
have been found must be carried out with care as these bodies are readily 
decomposed. In order to obtain the total alkaloidal content the pill or 
tablet should be ground up in a mortar and extracted with alcohol, the 
solvent cautiously evaporated until the liquid is in small bulk, treated 
with dilute sulphuric acid and filtered into a separator. Ammonia is then 



ALKALOIDS DERIVED FROM QUINOLIN 173 

added in excess and the alkaloids shaken out with chloroform, the latter is 
filtered into a tared dish, evaporated, the residue dried in a vacuum desic- 
cator and weighed as total mixed alkaloids. The quinin may then be 
estimated by the same procedure recommended for separating cocain aid 
strychnin described in detail under Nux Vomica alkaloids, page 52, the 
belladonna alkaloids being thereby destroyed and the quinin being 
recovered. 

If the analyst is working with a quinin morphin mixture the prelim- 
inary procedure will be similar to that already detailed, and then the 
quinin may be obtained alone by shaking it out with ether from a solu- 
tion made slightly alkaline with fixed alkali and the morphin obtained 
subsequently after acidulating, rendering ammoniacal and shaking out 
five times with chloroform-alcohol 2-1. 

QUININ FROM STRYCHNIN 

No very satisfactory method has yet been evolved for accurately and 
completely separating quinin and strychnin. This important mixture 
is quite common. It has been proposed to remove the strychnin as the 
ferrocyanide, but the precipitate invariably carries down with it a portion 
of quinin. Another procedure involves precipitating the quinin as oxa- 
late, but it has been found impossible to wash out the stiychnin without 
dissolving some of the quinin and it is impossible to separate the latter 
by means of a solvent when it occurs in a drug mixture with stiychnin. 

The methods in use for the separation and determination of quinin 
and strychnin in admixture are described under the Nux Vomica Alkaloids. 

The following titration method was devised by Buchbinder for mix- 
tures of quinin and strychnin, and the author believes that the same pro- 
cedure might be used for mixtures of quinin with such other alkaloids 
as give a neutral (to methyl red) hydrochloride and are not effected by 
treatment with acids. 

Dissolve the isolated alkaloid in alcohol; add a few drops of concen- 
trated hydrochloric acid and evaporate to apparent dryness on the water- 
bath. Dry in an oven at 110° until there is no reddening of a wetted 
piece of blue litmus paper held over it for a minute while in the oven. 
Dissolve in a little water and titrate with N/50 alkali. 

There is formed the dihydrochloride of quinin which is acid toward 
methyl red, the monohydrochloride being neutral. Difficulty is experi- 
enced in the recognition of the end-point, and this uncertainty is even 
more pronounced with the chloride than with the sulphate. However, 
with the aid of blanks, and after experience even without their aid, an 
accurate determination can be made. 

One mil of N/50 acid or alkali =6.49 mg. anhydrous quinin =7.57 mg. 
quinin-f-3H 2 = 8.73 mg. quinin sulphate +7H 2 0. 



174 ALKALOIDAL DRUGS 

Nishi l suggested a method for determining quinin by precipitating 
it as the citrate out of ethereal solution by means of an ethereal solution 
of citric acid, and Cockburn and Black 2 worked with it and considered it 
very accurate. The precipitated citrate after standing twenty-four hours 
is filtered onto asbestos, washed with ether and weighed. 

SEPARATION OF THE CINCHONA BASES 

Leger 3 has worked on the determination of quinin in mixtures with 
other cinchona alkaloids and proposed a method which he considers very 
accurate for mixtures of the sulphates of quinin, cinchonidin, and cin- 
chonin. The total alkaloids in the form of basic sulphates are treated 
with a boiling mixture of 5 mils of water and 75 mils of a solution of quinin 
sulphate saturated in the cold until completely dissolved and then set 
aside for twenty-four hours. In this way the sulphates of quinin and 
cinchonidin are separated and the sulphates of the other bases remain 
in the mother liquor. The crystalline sulphates are then filtered onto 
a Gooch, washed with saturated quinin sulphate and finally with 2 mils 
water, then dried spontaneously in the air, then at 30° C. and weighed. 
0.7 gram is then brought into solution in 40 mils of a boiling saturated 
solution of the tartrates of quinin and cinchonin, 2 mils of a sodium-potas- 
sium tartrate 35 per cent are added, and after twenty-four hours the pre- 
cipitate of double tartrates is collected on two counterpoised filters, 
washed first with saturated solution of cinchonidin and quinin tartrate, 
and then with 5 mils of water. The filters are drained and pressed between 
bibulous paper, the contents withdrawn and the filters and tartrates dried 
separately in the air and weighed. The index of rotation is then deter- 
mined according to Ondemann's formulae, 

215.8XzXl31.3(100-:r) = 100Xam, 

in which am = the observed rotation of the mixed tartrates. Hence 

x= — , in which 215.8 is the rotatory index of quinin tartrate 

.215 . o — lo .o 

and 131.3 that of cinchonidin tartrate. The quantity of quinin tartrate 

T. Q. in the mixed tartrates T.M. will be therefore 

= T.M. (100 am -13 130) 
^'~ 100(215.8-131.3) ' 

and the corresponding amount of quinin Q will be: 

324 X T.M. (100am- 13130) 
* 408X100(215.8-131.3) ' 

324 being the molecular weight of quinin and 408 that of its tartrate. 

1 Analyst, 1909, 34, 443. 2 Analyst, 1911, 36, 396. 

3 J. Pharm. Chim., 1904, 19, 427. 



ALKALOIDS DERIVED FROM QUINOLIN 175 

QUININ DERIVATIVES 
Aristochin. Diquinin carbonic ester. Aristoquin 

CO(C20H 2 3N 2 O2)2 

Aristochin occurs as a white, tasteless powder melting at \189°/ C, 
insoluble in water, sparingly soluble in alcohol and ether, and somewhat 
soluble in warm alcohol and chloroform. It combines with one and two 
molecules of hydrochloric acid to form soluble salts. Acids gradually 
decompose it with liberation of quinin. It is prepared by treating quinin 
dissolved in pyridin or chloroform with carbonyl chloride, or by heating 
together quinin and phenol carbonate in the proportion of 2-1. 

Chinaphenin 

Phenetidin quinin carbonic acid ester. 

CCKNHC6H4OC2H5) (C 2 oH 2 3N 2 02) 

This derivative is prepared by the action of quinin on p-ethoxyphenyl 
carbonic acid chloride. It is a white, odorless, tasteless powder, difficultly 
soluble in water, but readily soluble in alcohol, ether, chloroform, and 
benzol, and dissolving in acids to form salts. It is decomposed by acids 
with liberation of quinin. It gives the thalleoquin test and a yellow iodo- 
sulphate. 

Euquinin. Quinin Ethyl Carbonate. Euchinin 
C2H5OCOOC20H23N2O 

Alkyl esters of the cinchona alkaloid carbonic acids are prepared by 
heating the alkaloids with an alphyl ester of an alkylcarbonic acid. Thus, 
the ethyl ester of quinin carbonic acid is obtained by heating quinin with 
phenylethyl carbonate, dissolving the product in benzene, removing 
phenol by dilute ammonia, extracting the ethyl ester by a dilute acid, 
and precipitating by alkali. The product, C2H5O • CO • OC20H23N2O, 
forms white needles, which melt at 95° C, sparingly soluble in water but 
readily soluble in alcohol, ether, and chloroform. It is slightly alkaline 
in reaction and forms bitter salts with acids. Its solution in dilute sul- 
phuric acid is strongly fluorescent, it gives the thalleoquin test, but not 
the herapathite reaction. On warming with sodium hydroxide and iodine, 
iodoform is produced. 

Euquinin is practically tasteless and forms a tasteless tannate. 

Saloquinin 

Quinin Salicylic ester. Salochinin. Salicylquinin. 

When quinin is heated with phenyl salicylate (salol) in an oil-bath 



176 ALKALOIDAL DRUGS 

at 170-190° C, phenol distills and the quinin ester of salicylic acid remains. 
The product is dissolved in chloroform and shaken with 1 per cent acetic 
acid in order to remove unchanged quinin. 

OH • C 6 H4 • CO • OC6H5+C20H24N2O2 = 

C 6 H 5 • OH+OH • C 6 H4 • CO • OC2oH 23 N 2 0. 

The compound is a white crystalline, odorless and tasteless powder 
melting at 140° C, soluble in chloroform, hot alcohol, and benzene, little 
soluble in ether and cold alcohol. Ferric chloride colors the alcoholic 
solution reddish-brown. The corresponding cinchonidin compound melts 
at 65-70° C, its acid sulphate forms white needles which melt at 165° C. 
Its acid solutions are precipitated by alkalies and the usual alkaloidal 
reagents. 

Saloquinin salicylate is prepared by the addition of salicylic acid to 
a hot alcoholic solution of saloquinin. It is a white tasteless powder 
melting 182-183° C, sparingly soluble in water, soluble in benzol, chloro- 
form, and hot alcohol. 

Acid quinin dibromsalicylate, C 2 oH24N 2 022(C 6 H2Br20H • COOH) , 
known as Bromoquinol, occurs as yellowish crystals melting 197-198° C. 
and soluble with difficulty in water, alcohol, and ether. 

Quinin phytin 

This product is obtained by neutralizing anhydroxymethylene-diphos- 
phoric acid (phytin) with quinin and evaporating in vacuo. 

/ H 

/ \)— PO(OH) 2 
O C20H24N2O2 

\ /O— PO(OH) 2 
CH< 

It is a yellowish crystalline powder, bitter, soluble in water with fluores- 
ence, insoluble in alcohol, ether, benzol, and chloroform. It is an anti- 
pyretic. 

Quinin Lygosinate 

CO(CH : CH.C 6 H4-C 2 oH24N202)2 

Quinin lygosinate is prepared by the reaction of quinin hydrochloride 
with sodium lygosinate and is a quinin compound of dioxy-dibenzal-ace- 
tone. It is a bright orange-red amorphous powder, with a faint odor 
and bitter taste, melting at 114° C, slightly soluble in water, readily in 
alcohol, chloroform, and benzol, and decomposed by acids and alkalies. 



ALKALOIDS DERIVED FROM QUINOLIN 177 

It dyes cotton a bright yellow. On warming, the odor of benzaldehyde 
is developed. It may be separated into its constituents by shaking with 
alkali, removing the liberated quinin with ether, and on acidifying the 
lygosin separates as a yellow oil. 

It is employed as a styptic and bactericide, and applied as a dusting 
powder, on gauze, and in glycerin suspension. 

Guaiaquin. — Quinin Guaiacolbisulphonate, 

C6H4O2CH3HSO3C20H24N2O2, 

is a yellow, bitter powder soluble in water, alcohol and dilute acids. 

Guaiaquinol. — Quinin Dihydrobromoguaiacolate, C20H24N2O2 • 2HBr • 
C6H4OHOCH3, occurs as yellow hygroscopic crystals, readily soluble in 
water. 

Quinaphthol. — Quinin betanaphthol monosulphonate, 

C2oH 2 4N20 2 (OHCioH 6 S0 3 H) 2 , 

is a yellow crystalline powder, melting 185-186° C, soluble in alcohol 
and hot water. 

Quinin Eosolate (CgH7S30i2)(C2oH24N202), is the neutral salt of tri- 
sulphoacetyl guaiacol, a yellow, bitter amorphous powder, soluble in alco- 
hol and slightly in water. 

Quinin Ethyl Sulphate or Sulphoninate C20H24N2O2C2H5SO4, occurs 
in white crystals readily soluble in water. 

J. Hesse has recently prepared a new compound of phenol with quinin 
bisulphate. If carbolic acid be added in equivalent proportion to a 
hot aqueous solution of quinin bisulphate, on cooling at first an oily 
mass separates out, above which delicate white needles are gradually 
formed, of the composition C20H24N2O2SO3C6H6O+3H2O. This com- 
pound is very unstable. If it be dissolved in hot water, on cooling the 
first named normal salt crystallizes out. Quite in accordance with this 
is the behavior of the acid quinin resorcinol sulphate, the acid quinin 
quinol sulphate, the acid quinin pyrogallol sulphate, and the acid cin- 
chonidin pyrogallol sulphate. The author further prepared and de- 
scribes the normal quinin orcinol sulphate, quinin catechol sulphate, cin- 
chonidin quinol sulphate, as well as the quinin resorcinol, quinin catechol, 
and quinin pyrogallol hydrochlorides. They are beautifully crystallized 
compounds and some of them excellent febrifuges. - 

YOHIMBE, QUEBRACHO, PSEUD OCINCHONA AFRICANA, ANGOSTURA, 
ALSTONIA, GEISSOSPERMUM 

The barks of several trees belonging to the Rubiacese, Apocynacea* 
and Rutacese are credited with febrifugal, tonic, and aphrodisiac proper- 



178 ALKALOIDAL DRUGS 

ties. The drugs contain alkaloids possessing properties which in some 
instances are quite similar to each other, but as yet they have not been 
classified chemically. To avoid confusion, the data have been assembled 
under one heading, and placed next to Cinchona. Some of the drugs 
resemble Cinchona in appearance, and the alkaloids derived therefrom 
have similar physiological properties, though their chemical reactions are 
often more like those of the Nux Vomica bases. 

The botanical identity of the plants from which the drugs are derived 
is not conclusive in every case, neither is the identity of the bases, as cer- 
tain of the latter bear a close relation to each other and are perhaps iso- 
meric or even identical. 

These drugs are employed as bitter tonics, nerve tonics, and aphro- 
disiacs, and will be found in small amounts in alcoholic liquids recom- 
mended for recuperative and restorative purposes, often in combination 
with Turnera aphrodisiaca (Damiana). 

ALKALOIDS OF YOHIMBE BARK 

The bark of the Yohimbe or Yumbehoa tree, Corynanthe Yohimbe 
(Rubiacese), contains yohimbin and other bases as yet unstudied. 

The especial microscopic characteristic of yohimbe bark is the struc- 
ture of the secondary bark, which contains numerous yellowish-white 
bast fibers, regularly arranged, distinguishing yumbehoa bark from cin- 
chona bark, otherwise similar. The powdered bark (fine and moder- 
ately fine only are considered) is characterised by (1) the numerous pore- 
free bast fibers, with complete absence of stone cells, (2) the presence of 
greatly thickened porous and almost pigment-free cork cells, (3) the brown- 
walled, almost starch-free parenchyma, together with reddish-brown lumps 
of coloring matter. Cinchona barks are distinguished by the appearance 
of their bast fibers; cinnamon bark by the color, presence of stone cells, 
and high starch content. 

Yohimbin 

This alkaloid, which seems to be the chief base of the Yohimbe group, 
has been the subject of considerable research, though as yet its constitu- 
tion is undetermined. Its formula has not been definitely settled, but 
it appears to be either C22H28N2O3 or C21H26N2O3. The latter value is 
the same as that determined for corynanthin, the alkaloid of Pseudocin- 
chona africana, and quebrachin. The latest researches indicate that 
corynanthin is isomeric with yohimbin and dextro-quebrachin. 

When yohimbin is heated two hours with alcoholic potash, a methyl 
group is split off and the potassium salt of an acid remains in solution, 
which crystallizes from water in glassy prisms. This body is called nor- 
yohimbin or yohimboaic acid and forms salts with both bases and acids. 



ALKALOIDS DERIVED FROM QUINOLIN 179 

Yohimbin is not simply a methyl ester of yohimboaic acid, esterification 
with different alcohols shows that two alkyl groups are taken up and one 
molecule of water is split off. 

Corynanthin is also a methyl derivative, and on saponification yieids 
an acid having the same composition as yohimboaic acid. 

Yohimbin crystallizes in the dark from absolute alcohol in anhydrous 
white needles melting at 247-248°. It is dextrorotatory, readily soluble 
in alcohol, ether, and chloroform, slightly in petroleum ether, benzol, and 
water. Its salts with hydrochloric and nitric acids are used in medicine, 
the latter being but sparingly soluble in water. 

Yohimbin residues give two reactions which deserve special consider- 
ation on account of their resemblance to those of stiychnin, and which 
might lead to confusion and possibly erroneous conclusions if the analyst 
has but a small quantity of material at his disposal. On adding sulphuric 
acid to a residue, a yellow color is obtained, which on adding potassium 
bichromate becomes purple, changing to blue, red, and finally green; if 
the quantity is considerable the first color is indigo-blue, changing rapidly 
to olive-green. Nitric acid gives a yellow solution, which becomes orange 
on evaporation; this residue treated with alcoholic potash yields a pur- 
ple color momentarily, then chocolate and on warming almost black; as 
the last portions of alcohol evaporate there is an odor of orange-flower. 
Yohimbin residues do not have the intense bitter taste that is character- 
istic of strychnin, and they are readily distinguished by the microscopic 
forms of the salts formed with gold chloride and other reagents used in 
the identification of stiychnin. 

A solution of yohimbin in concentrated sulphuric acid gives an intense 
orange with calcium hypochlorite. Formaldehyde-sulphuric gives a dark 
brown color. 

Yohimbin gives precipitates with most of the alkaloid precipitants, 
most of the compounds are amorphous, including those with gold and pla- 
tinic chloride. Chromic acid precipitates a mass of fine yellow crystals sol- 
uble in ammonia. Picric acid throws down yellow microscopic crystals 
which soon agglomerate and stick to the sides of the container. An alcoholic 
solution gives a white precipitate with bromine water. The precipitate 
obtained with mercuric chloride is crystalline and dissolves in water when 
the solution is diluted. Nessler's reagent gives a white amorphous pre- 
cipitate and reduction takes place with ammoniacal silver nitrate. 

Yohimbin hydrochloride is an anesthetic, but there is no likelihood 
of confusing it with cocain hydrochloride, after precipitating the alkaloid 
and subjecting it to the proper tests for identification. 

The alkaloidal residue from yohimbe bark probably contains one or 
more bases in addition to yohimbin. 



180 ALKALOIDAL DRUGS 

QUEBRACHO ALKALOIDS 

The bark of Aspidosperma Quebracho-bianco (Apocynacese) contains 
aspidospermin, aspidospermatin, aspidosamin, quebrachin, hydro-que- 
brachin, and quebrachamin. The drug is not of common occurrence 
in medicine, though the extract is used extensively in tanning, and the 
composition and properties of the bases have been subjected to but little 
research. Quebrachin probably occurs in the racemic, lsevo, and dextro 
forms, the latter being apparently identical with yohimbin. 

The reactions of the bases may be summarized as follows: 

Aspidospermin with sulphuric acid and lead peroxide gives a brown 
color changing to purple-red. When boiled with perchloric acid an intense 
red color results, the reaction probably depending on the presence in the 
acid of impurities having oxidizing power. Platinic chloride gives a blue 
precipitate which becomes violet on boiling with excess of the reagent. 
Potassium chromate produces a yellow precipitate which turns green on 
exposure to air. 

Hydro-quebrachin gives a yellow color with sulphuric acid, and the 
same reaction with perchloric acid as aspidospermin. The chloroplatinate 
is yellow and dissolves in boiling hydrochloric acid with a brown red color, 
depositing a blue precipitate on standing. 

Quebrachin gives a bluish solution with sulphuric acid, turning blue 
and brown with bichromate. With perchloric acid the color is yellow. 

Quebrachamin gives a violet color with sulphuric acid and bichromate 
and a yellow to yellowish-red with perchloric acid. 

Aspidospermatin gives with perchloric acid the same color as aspi- 
dospermin, but the precipitate with platinic chloride is yellow. 

Aspidosamin gives a brown color with sulphuric acid, turning blue 
with bichromate, and a fuchsin red color with perchloric acid. 

ALKALOID FROM PSEUD O CINCHONA AFRICANA 

Chevalier in 1897 called attention to a bark used for febrifugal pur- 
poses by the natives on the Ivory Coast. Its botanical identity was 
unknown, but from its resemblance to Cinchona he gave it the name Pseu- 
docinchona africana. Further study showed that it contained at least 
two alkaloids, one of which was crystalline and is probably isomeric with 
yohimbin, and the other amorphous. The former has been called cory- 
nanthin. On demethylation it yields an acid-like body apparently iden- 
tical with yohimboaic acid, and in other respects it bears a close relation- 
ship to yohimbin. It crystallizes from absolute alcohol in colorless hex- 
agonal plates, and from 60 per cent alcohol in elongated spangles with 
water of crystallization. It melts 241-242°, has [a] D -125° at 23° with the 
composition C21H26N2O3, which makes it isomeric with dextro-quebrachin. 



ALKALOIDS DERIVED FROM QUINOLIN 181 

It is insoluble in petroleum ether, water and alkalies, but dissolves with 
greater or less facility in the organic solvents. It gives a blue color with 
sulphuric acid and bichromate, but its color tests have not been thoroughly 
studied. The characteristics of the bark from which it is derived have 
not been authentically reported. 

THE ANGOSTURA ALKALOIDS 

The bark of Cusparia officinalis, syn. C. trifoliata contains several alka- 
loids which have been studied by Troger and others. The isolated bases 
have never been employed for medicinal purposes, but an extract of the 
bark has a limited use as a tonic and febrifuge and will be found occasion- 
ally as an ingredient of bitters and restoratives. 

Troger x mentions five bases occurring in the drug: galipoidin, melt- 
ing 231°; cusparidin, melting 79°; galipidin, melting 111°; galipin, melt- 
ing 115°; and cusparin, melting 89-90°. He concludes that galipin and 
galipidin are dihydro compounds of cusparin and cusparidin respectively. 
In a previous article 2 he describes cusparein, melting 55-56°, and angos- 
turin, melting 231-233°. Later 3 he says that, besides certain oily bases, 
the extract of angostura bark contains only cusparin, galipin, and galipidin. 
Galipin was separated from cusparin by the difference in the solubility 
of the oxalates, that of galipin being readily soluble in water and crystalliz- 
ing only at considerable concentration, cusparin oxalate being soluble 
only in a considerable excess of boiling water. 

Galipin on oxidation with permanganate yields veratric and methoxy- 
quinolincarboxylic acids. 

The alkaloidal residue when dissolved in sulphuric acid and treated 
with a crystal of permanganate gives a reaction resembling that of 
strychnin. 

ALKALOIDS OF THE ALSTONIA BARKS 

Alstonia constricta (Apocynacese) of Queensland and New South 
Wales and A. scholaris, known as Dita bark of the Philippines, have been 
used in dysentery and intermittent fevers. 

The bases of the former, alstonin, melting about 195°, and porphyrin, 
melting 97°, show a blue fluorescence in acid solution and might be mis- 
taken for quinin. 

Hesse examined the Dita bark and found three bases, ditamin, echi- 
tamin, and echitenin. The second is a strong base and resembles ammonia 
in its chemical characters. Hesse considers the compound given by echi- 
tamin with one molecule of water as the hydroxide of a strong basic radicle, 

1 Arch. Pharra., 240, 174. 2 Apoth. Zeit., 25, 957, 969, 977, 988. 

3 Arch. Pharm., 250, 494. 



182 ALKALOIDAL DRUGS 

echitammonium. The solutions are so strongly basic that they precipitate 
the hydroxides of copper, iron, aluminum, and lead, and decompose sodium 
and potassium chlorides, liberating the corresponding hydroxides. 

ALKALOIDS OF GEISSOSPERMUM 

The following bases have been isolated from the bark of Geissosper- 
mum vellosi (Apocynaceae), pereirin, melting 124°, geissospermin, and 
vellosin. The melting-point of geissospermin has been reported as 160° 
and as 189°, consequently the chemistry of this group is somewhat con- 
fusing. Under the name Pao-pereira this bark is used in Brazil as a 
febrifuge. 

With the possible exception of yohimbin, the known reactions of the 
bases described under this group of drugs are, from an analytical stand- 
point, very meager and unsatisfactory, and capable of misinterpretation. 
In forensic w x ork the advantage is all on the side of the chemist who is 
working for the party that knows the ingredients of the mixture in. ques- 
tion, and he can of course plan his tests and interpret his reactions accord- 
ingly. With the chemist who takes the product as an unknown mixture 
the problem is entirely different, and as these preparations usually con- 
tain but a meager quantity of the drug, by the time he has come to dif- 
ferentiate between the several possible bases, he will find that his material 
is exhausted. To the analyst who finds himself in this position a few 
words of caution are necessary; the first is not to confuse those bases 
with strychnin and the second is to refrain from stating positively the 
source of the alkaloids found unless he has worked with knowm specimens 
side by side with the sample under investigation and is prepared to meet 
all possible criticisms from his adversaries. It is a simple matter to iden- 
tify strychnin, as it yields several well-defined crystalline salts with alka- 
loidal precipitations, all of which can be easily identified under the micro- 
scope, w T hile the precipitates given by the bases herein described are mostly 
amorphous. If strychnin occurs with these bases it is more than possible 
that the analyst will miss the latter and come in for a round of undeserved 
criticism and sarcasm from the opposition when the case is summarized. 



CHAPTER VII 



ALKALOIDS DERIVED FROM ISOQUINOLIN 
THE OPIUM ALKALOIDS AND THEIR DERIVATIVES 



Morphin, C17H19NO3 
Codein, C18H21NO3 
Pseudomorphin, (Ci7HisN03)2 
Thebain, C19H21NO3 
Papaverin, C20H21NO4 
Codamin, C20H25NO4 
Laudanin, C20H25NO4 
Laudanidin, C20H25NO4 
Laudanosin, C21H27NO4 
Tritopin, (C 2 iH 2 7N0 3 )20 



Meconidin, C21H23NO4 
Lanthopin, C23H25NO4 
Protopin, C20H19NO5 
Cryptopin, C2iHi 3 N05 
Papaveramin, C21H21NO5 
Narcotin, C22H23NO7 
Gnoscopin, C22H23NO7 stereoisomer 
Oxynarcotin, C22H23NO8 
Hydrocotarnin, C12H15NO3 
Xanthalin, C20H19NO5 



The average relative proportions of some of these bases in the drug 
are approximately as follows: 



Per Cent 

Morphin 9 

Narcotin 5 

Papaverin 0.8 

Thebain 0.4 

Codein 0.3 

Narcein 0.2 

Cryptopin . 08 Laudanosin . 



Per Cent 

Pseudomorphin. . . .0.02 

Laudanin 0.01 

Lanthopin 0.006 

Protopin 0.003 

Codamin 0.002 

Tritopin 0.0015 

...0.0008 



OPIUM 

The opium used in the manufacture of morphin and its accompany- 
ing alkaloids and for pharmaceutical preparations comes almost exclu- 
sively from Turkey and Asia Minor. It is the exuded juice of the black 
poppy (Papaver somniferum), which is gathered in a partially dry, gummy 
mass and sent into the trade in cakes of from 1 to 4 lbs. These cakes are 
usually wrapped with poppy or dock leaves and packed in cases with layers 
of dock capsules. The customs officials become very expert in the sam- 
pling of opium by the eye alone, and can tell by simply cutting into a cake 
whether it contains excessive moisture or extraneous substances, and is 

183 



184 ALKALOIDAL DRUGS 

of high or low grade. It is regarded as inferior if it is blackish in color, 
has a weak or empyreumatic odor, a sweet or slightly nauseous and bitter 
taste, a soft, viscid, or greasy consistency, a dull fracture, or an irregular 
appearance from the admixture of foreign substances. In the case of 
good opium, the lumps are usually hard on the outside, but still soft 
within, the internal color being light brown, and the interior containing but 
few, if any, dock capsules. On cutting open and tearing apart the lump, 
numerous minute shiny tears will sometimes be observed. The odor is 
pleasant and characteristic. 

Opium is adulterated with chunks of lead, stones, bullets, sand, clay, 
and other weight-producing substances, sugar, starch, tragacanth, fruit 
pulp, extract of licorice, poppy, and other plants and vegetable substances 
of a resinous or saccharin nature; and if it has been kept under damp 
conditions it will have become moldy. The composition of good opium 
is about as follows: 

Per Cent 

Moisture 8-30 averaging 20 

Ash 4-8 

Gum and soluble substances other than alkaloids. 40-60 

Morphin 6-15 

Narcotin 4-8 

Other alkaloids 0.5-2 

Meconic acid 3-8 

Resins 5-10 

Fat 1- 4 

and it should yield 55-60 per cent of extractive matter to cold water 
based on the dry product. 

Smoking opium is no longer imported legitimately, but it is probably 
illegally made in this country, and smuggled in to a limited extent. The 
product is an aqueous extract of opium evaporated down to the con- 
sistency of a thick molasses, and is similar in every way to the old U. S. P. 
extract of opium. Smoking opium from China averages about 6.5 per 
cent morphin, while that made from Smyrna gum runs from 16 to 18 per 
cent. 

The sampling of opium requires considerable care, as the determi- 
nation of the value or condition of the entire lot or case is often dependent 
on the assay. Squibb recommends that every fifth lump should be taken, 
except the very small ones, and then every tenth lump of these be sepa- 
rated, a cone-shaped piece cut from each, the apex of the cone being near 
the center of the lump. A narrow strip is then cut from the side of each 
cone, the strips collected together in a cone, and this sample used for the 
determination of the moisture and morphin. The methods of assaying 
opium for its morphin content are described in the chapter on Drug 
Assays. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 185 

Kerbosch 1 has made an interesting investigation of the occurrence and 
distribution of certain of the alkaloids in the poppy plant. The seeds con- 
tain traces of narcotin and an amorphous alkaloid and three days after 
germination notable quantities of narcotin are present, soon followed 
respectively by codein, morphia, papaverin, and thebain. The flowering 
plant up to the time of ripening contains narcotin, papaverin, codein, and 
morphin in all its organs with the exception of the hairs. The latex 
varies in composition in different parts of the plant. 

Morphin, codein, meconidin, codamin, laudanin, laudanidin, laudano- 
sin, protopin, and cryptopin are all strong bases and narcotic or tetanic 
in their action, the others are weak bases and have little or no poisonous 
activity. They are present in the drug in acid combination to a large 
extent, the acid radicles being chiefly meconic and sulphuric. The drug 
analyst will seldom be concerned with the identification or determination 
of the entire list. Morphin, codein, thebain, narcotin, narcein, and papa- 
verin are the only individuals with which familiarity is necessaiy, and in 
addition to these bases meconic acid is of moment, as its identification is 
an important factor in establishing the presence of opium in a preparation. 
The recognition of this group is easy, either alone or in mixtures. 

In medicinal preparations one will find that morphin, opium extract, 
and codein, and in addition to these some of the derivatives, heroin, apo- 
morphin, and dionin, are used to a considerable extent. They are all use- 
ful for diminishing pain and inhibiting secretions except that of the skin, 
and are generally narcotic and will be found in cough mixtures, lozenges, 
and soothing syrups, diarrhea mixtures, neuralgia remedies, anodynes, 
coryza mixtures, consumption remedies, habit cures, and in a variety of 
imported foreign drug products, notably Chinese remedies. Several prod- 
ucts having a household reputation contain these bases, among which 
may be mentioned Dover's powder, paregoric, laudanum, sun cholera 
mixture, brown mixture, white pine cough syrup, and chlorodyne. 

Considering the products separately, opium will be found alone in 
laudanum or tincture of opium, fluid opium, wine of opium, and some 
elixirs of a similar nature having different trade-marked names, " cures " 
recommended for the opium habit, and in pills. It occurs in combi- 
nation with camphor, oil of anise, and glycerin in paregoric, or camphor- 
ated tincture of opium,- this combination being in some respects similar 
to the well-known proprietary " Bateman's Pectoral Drops," which also 
has been made up to include catechu. It is a constituent of ammoniated 
tincture of opium, similar to paregoric except that camphor is replaced 
by dilute ammonia. Black drop is essentially an acetic acid solution of 
the constituents of opium. It is combined with potassium carbonate, 
oil of sassafras, and molasses in a type of mixtures resembling Godfrey's 
1 Arch. Pharm., 1910, 248-336. 



186 ALKALOIDAL DRUGS 

Cordial; with magnesium carbonate, anise, nutmeg, peppermint, and 
castor oil in products of the Dalby's Carminative type; and in tinctures 
combined with ipecac. Opium in powdered form is mixed with powdered 
ipecac in the well-known Dover's powders, and with pepper, ginger, and 
caraway in compound opium powder. The different pill and tablet com- 
binations in which opium occurs are numerous, -some of the more common 
being with ipecac and mercury mass; asafetida and ammonium carbon- 
ate; calomel, camphor, and lead acetate, or in place of the latter tannin 
or hyoscyamus; guaiac and mercuric chloride; mercurous iodide, lead 
acetate, phosphorus, Digitalis with and without quinin or ipecac; ipecac, 
quinin and belladonna; licorice, benzoic acid, camphor, tartar emetic and 
anise in brown mixture; calomel and ipecac; copper sulphate, ipecac, 
and squills; potassium iodide, potassium arsenite, Lobelia, and belladonna 
in asthmatic remedies; bismuth subnitrate and carbolic acid; quinin, 
ammonium chloride, camphor, belladonna, and aconite; Krameria, bis- 
muth subnitrate, and licorice; Hyoscyamus, Hamamelis, tannin, thymol, 
helonias, salicylic acid, boric acid, alum, and eucalyptol in leucorrhea mix- 
tures; white pine, wild cherry, squill, senega, ipecac, Sanguinaria, potas- 
sium nitrate, and methyl salicylate; capsicum, rhubarb, camphor, and 
oil peppermint in sun cholera mixture; terpin hydrate, guaiac, wild cherry, 
and belladonna; aloin, Capsicum, aconite, quinin, ipecac, and calomel in 
cold remedies; and quinin, ammonium chloride, camphor, belladonna and 
aconite. This list does not by any means cover the field of combinations, 
new formulas are constantly being introduced, but it will show in a general 
way the type of mixtures on the market, and the class of substances with 
which opium is combined. Opium should be looked for also in supposi- 
tories, in admixture with tannin, menthol, camphor, and boric acid, and 
in ointments recommended as local applications for croup and pneumonia 
where it occurs with quinin, camphor, phenol, and turpentine. 

Morphin in the form of sulphate, hydrochloride, nitrate, meconate, 
tartrate, phthalate, and valerianate, occurs alone in pills and tablets and 
will sometimes be found in snuff powders and as a remedy for the mor- 
phin habit. It also occurs as the oleate. Morphin sulphate and atropin 
sulphate in various proportions are combined in hydopermic tablets to a 
large extent; and it is used in conjunction with cocain in dental tablets, 
and to a limited amount with strychnin. It is also present in place of 
opium in some of the mixtures mentioned above ; chlorodyne mixture con- 
tains morphin hydrochloride, nitroglycerin, Cannabis, Hyoscyamus, Cap- 
sicum and peppermint; morphin bromide compound contains morphin 
and scopolamin (" hyoscin ") hydrobromates with monobromated cam- 
phor; uterine astringent and antiseptic tablets consist of alum, zinc sul- 
phate, tannin, boric acid, morphin sulphate and extract Hydrastis; medi- 
cated lozenges contain ipecac and morphin sometimes with other ingredi- 



ALKALOIDS DERIVED FROM ISOQUINOLIN 187 

ents; white pine compound, a liquid cough remedy contains morphin 
acetate, sassafras, Sanguinaria, spikenard, wild cherry, white pine bark 
and balsam of poplar buds and sometimes chloroform and tar are used; 
morphin sulphate will be found in combination with laxative drugs in 
liquid preparations sold as cures for the morphin habit. 

Codein has a much more restricted use than opium or morphin, but 
the combinations in which it does occur are sold to a large extent. It 
occurs alone in pills and tablets and in hypodermic tablets, especially as 
the phosphate and is often combined with acetanilid, caffein, bromides 
and sodium salicylate; with antipyrin, spartein, strophanthus and caffein; 
and with colchicin and sodium salicylate. In the liquid form it is mixed 
with acetanilid, caffein, and bromides, and often replaces morphin in 
cough mixtures of the white-pine type. It is said to have been used to 
some extent in confectionery sold for throat troubles. 

Heroin is employed as a substitute for morphin in cough mixtures and 
is also mixed with terpin hydrate in elixirs, and sold alone in tablet tritu- 
rates and hypodermic tablets. 

Apomorphin is employed chiefly in the form of hypodermic tablets. 

The other alkaloids of opium or their derivatives are either used by 
themselves or have no commercial use other than in their extract form. 

Morphin 

CH 3 

H H 2 | 
C C N 



HC C CH CH 2 

I II I I 
HOC C C CH 2 

V V \/ 

C C CH 

I I I 

O C CH 2 



H C 

/\ 
H OH 

Morphin crystallizes out of alcohol in prisms containing one molecule 
of water. It is lsevorotatory, slightly soluble in water, ether, chloroform, 
and benzol, but readily soluble in alcohol, alcohol-chloroform mixture, 
amyl alcohol, acids, and alkalies. Its water of hydration is given off at 
100° and the alkaloid melts at 254° C. when heated rapidly. When heated 
slowly it begins to melt at 247° with decomposition. Morphin with its 
water of hydration melts at about 230° C. 



188 ALKALOIDAL DRUGS 

It is a strong tertiary base and also a monatomic phenol, dissolving in 
alkalies to form salts with one atom of the metal which are decomposed 
by carbon dioxide or ammonia. This property of forming salts with alka- 
lies is used to good advantage in separating morphin from other alkaloids. 
It forms diacetyl and dibenzoyl derivatives. On strong oxidation with 
dilute nitric acid it gives a dibasic acid, C10H9NO9, and this on further 
treatment with fuming nitric acid is converted into picric acid. On methyl- 
ation it is changed to codein, the group being introduced on the phenolic 
hydroxyl. Thebain may be considered as oxymethyl codein and the rela- 
tionship of these three bodies may be represented as follows : 



r— oh 


r — 0CH3 




f — OCH3 


C15H14ON — CHOH 


C15H14ON —CHOH 


C15H14ON ' 


— COCH3H 

II 

I — CH 


[— CH 2 


I— CH 2 




Morphin 


Codein 




Thebain 



When fused with potassium hydroxide morphin gives protocatechuic 
acid. Acids, alkalies, and zinc chloride remove a molecule of water and 
convert it into apomorphin, which is soluble in ether and chloroform. 

Morphin is readily oxidized even by gold and silver salts, and iodic 
acid. On oxidation by weak oxidizing agents, pseudomorphin is formed 
according to the reaction, 

2Ci 7 Hi 9 N0 3 +0 = (Ci 7 Hi 8 N03)2+H 2 

It is precipitated by the usual alkaloidal precipitants, but not by potas- 
sium chromate or ferrocyanide, and gives some interesting color tests both 
in aqueous solution and as a dry residue. A neutral aqueous solution gives 
a deep blue-green color with ferric chloride, changed to green with excess 
of the reagent and disappearing on the addition of acids or alcohol or on 
heating. Pseudomorphin gives a blue color and codamin a dark green. 
An aqueous solution reduces iodic acid with liberation of iodin, which 
will dissolve in carbon bisulphate or chloroform with a violet color. Mor- 
phin will reduce potassium ferricyanide, being itself oxidized to pseudo- 
morphin, and if an aqueous solution slightly acidified is added to a solution 
of potassium ferricyanide and ferric chloride a blue precipitate or color- 
ation will be produced due to the formation of Prussian blue. 

Iodic acid followed by ammonia gives a mahogany color which is a 
positive test, while the simple reduction is not necessarily characteristic 
of morphin. Iodic acid is reduced by extractive matter from animal tis- 
sues, some medicinal drugs and inorganic compounds. The iodic acid 
ammonia test, however, is distinctive according to Peterson and Haines; 



ALKALOIDS DERIVED FROM ISOQUINOLIN 189 

they report its application to numerous extracts from putrefied animal 
matter of various kinds, and in no case was a fallacious indication 
obtained. 

The iodic acid test may be applied directly to a dry residue on a smooth 
porcelain surface. A drop of the reagent is added to a small quantity of 
the suspected residue and after standing ten minutes, any iodin is washed 
off by floating over it a drop or two of chloroform, repeating until the spot 
is colorless. When dry a drop or two of 10 per cent ammonia water is 
added, when a mahogany color indicates morphin. The decanted chloro- 
form is then evaporated and tested with a little starch paste, which will 
turn blue if free iodin is present. 

Strong nitric acid added to solid morphin turns it a deep red or orange- 
red color, the crystals dissolving to an orange-red solution, gradually fading 
on standing. A drop of stannous chloride added to the red solution pro- 
duces no change, differing from the brucin nitric acid color which thereby 
is changed to purple. Strong sulphuric acid gives only a faint pink color 
with morphin when both substances are pure, and the color soon fades. 
If a solution in concentrated sulphuric acid is warmed to 100° C. and then 
treated with concentrated nitric acid, a chlorate, chlorin water or sodium 
hypochlorite, a blue or purplish color is obtained, passing to deep red and 
gradually fading. This is known as Husemann's test and is very delicate. 
Chloral or bromal added to a solution of morphin in strong sulphuric 
acid, produce a deep purple color and Froehde's reagent a deep purple 
fading to slate. Ammonium persulphate in sulphuric acid gives pale 
orange. 

If morphin is treated with a little sugar, moistened with a drop of water 
and made into a paste and a drop of sulphuric acid is allowed to flow 
alongside the mixture, an intense purple color will develop at the point 
of contact, changing to violet and green to yellow 

With bichromate and sulphuric acid a greenish color is produced and 
with vanadium-sulphuric acid, colors from yellow, passing to violet brown 
and slate are obtained. 

A dilute solution of morphin treated with 1 mil each of 3 per cent 
hydrogen peroxide and dilute ammonia, followed by 1 drop of copper sul- 
phate solution 1-4 per cent gives a color varying from rose to red. Deniges 
recommends this reaction in testing for morphin directly. 

Apomorphin and oxymorphin react in a similar manner in syrups, but 
codein, thebain, papaverin, narcein, and narcotin give negative results. 

Solutions of morphin give characteristic crystalline precipitates with 
iodin solution, palladous chloride, picrolonic acid and other reagents and 
a microscopical examination of the forms of these compounds is one of 
the most valuable means of identifying the base and distinguishing it 
from its allies. 



190 ALKALOIDAL DRUGS 

If morphin is dissolved in hydrochloric acid, a little sulphuric acid 
added and the mixture evaporated on an oil-bath at a temperature of 
100-120° a purple color appears on the edges, and after the volatile acid 
is all evaporated a red color remains. On dissolving again in hydro- 
chloric acid and neutralizing with sodium bicarbonate a violet color is 
obtained. If hydriodic acid is added the color changes to green and on 
shaking with ether, the solvent becomes purple. 

When morphin is mixed with hydrastin and treated with a little con- 
centrated sulphuric acid, a faint pink color is given which soon fades, and 
then very gradually a reddish purple shade develops, which after some 
time changes to green. If a crystal of bichromate is added as soon as the 
mixed alkaloids have dissolved in the acid, a slate color appears, chang- 
ing to indigo blue and then to a deep purple which is quite permanent 
for some time and then gradually passes to brown. This test has become 
known as the Lloyd reaction, and might under some circumstances be 
mistaken for a strychnin test. However, neither morphin nor hydrastin 
give a purple color when evaporated with nitric acid and treated with 
alcoholic potash, which happens with strychnin. It is stated that the 
veratrum alkaloids when mixed with hydrastin and treated with sulphuric 
acid will give a violet color. 

Morphin is not removed from acid aqueous solution by solvents, and 
from alkaline liquids is extracted only by amyl alcohol or an alcohol- 
chloroform mixture. If the solution is made alkaline with ammonia 
under ordinary conditions minute amounts will be taken up by ether and 
chloroform, but in the presence of sodium or potassium hydroxide it is 
insoluble, and may thus be separated from most of the other alkaloids. 
It has been shown that an acid solution of morphin containing a little 
alcohol, saturated with sodium chloride and rendered alkaline with a slight 
excess of ammonia, will give up its morphin by shaking six to ten times 
with chloroform. It is well known that alkaloids in the freshly precipi- 
tated, or so called " nascent " condition, are far more readily soluble than 
when they have been allowed to crystallize. Morphin when dissolved 
in chloroform may be removed from this solvent by solutions of the caustic 
alkalies. 

Alkyl derivatives of morphin are easily produced by dissolving the 
base in alcohol and heating for two hours under a reflux condenser in the 
presence of the alkyl sulphate of potassium or sodium. 

Carbonic esters may be prepared by dissolving morphin in alcohol, 
adding alcoholic alkali and a slight excess of the alkyl chloro-carbonate. 
The reaction takes place at once with rise of temperature. The mixture 
is then neutralized with sulphuric acid, the alcohol distilled off, the resi- 
due dissolved in water and the ester of morphin carbonic acid liberated 
by alkali, and dissolved out in benzol. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 191 

Of the salts of morphin the acetate, hydrochloride and sulphate will 
be encountered most frequently. Morphin acetate contains three mole- 
cules of water and occurs as a white or yellowish powder, very soluble in 
water and partially decomposed on boiling or evaporating. Morphin 
hydrochloride contains three molecules of water which are lost at 100° C. 
The crystalline salt is in white needles or minute cubes. The sulphate 
containing five molecules of water is probably the compound which has 
the widest use. It crystallizes in bundles of silky needles, and as found 
on the market is usually in small cubes. It loses 3H2O at 100° and the 
remainder at 110°. Tin's is the form used to a large extent in making 
hypodermic tablets; for sale in J-ounce vials to those addicted to the habit; 
for mixing with sugar and other inert substances in snuffs; and for cough 
mixtures, and various pill and tablet formulas. It has been observed that 
commercial morphin sulphate sometimes contains an appreciable quantity 
of codein. This is due to imperfect methods of manufacture and is not 
an intentional adulteration. 

There are many other salts of morphin on the market but their use 
is comparatively limited. 

Morphinmethylbromide 

This product, known also as morphosan, closely resembles morphin 
in some of its properties. It forms white needle-shaped crystals, readily 
soluble in water, slightly in alcohol, and almost insoluble in ether and 
chloroform. It becomes anhydrous at 100-110°, and melts with decom- 
position at 264-265°. Its solutions give a blue color with ferric chloride 
and a blue precipitate with ferric chloride and potassium ferricj^anide. 
It dissolves in sulphuric acid with a yellow color, and in Froehde's reagent 
with a violet color soon changing to dark green. Nitric acid produces 
a blood-red color, and formaldehyde sulphuric a red-violet changing to 
blackish green. Its solution is not precipitated by ammonia and it gives 
a test for bromine on decomposing with nitric acid in presence of silver 
nitrate. 

Codein. C 17 H 18 (CH3)N03 

Codein or methyl morphin occurs in white prismatic crystals. It 
crystallizes from water with one molecule of the solvent and melts under 
boiling water to an oily liquid. Anhydrous codein melts at 155°. It is 
fairly soluble in water, especially when hot, and also in ammoniacal solu- 
tions, the latter property distinguishing it from morphin and useful in 
separating it from that base. It is readily soluble in alcohol, chloroform, 
benzol, ether, and amyl alcohol. It is practically insoluble in petroleum 



192 ALKALOIDAL DRUGS 

ether and only slightly soluble in fixed alkalies. Its solutions are alka- 
line in reaction and lsevorotatory. 

With dehydrating agents, codein either forms condensation products, 
or loses a molecule of water and is converted to apocodein, C18H19NO2. 

Codein resembles morphin in some of its color reactions, but is sharply 
distinguished from it in others, and in its solubility in the ordinary organic 
solvents. With sulphuric acid no color is produced but if a trace of arsen- 
ate, dilute nitric acid, or ferric chloride is present, a blue color is produced. 
With nitric acid a yellow color is obtained, the crystals assuming an orange 
color until dissolved. Formaldehyde-sulphuric acid gives a deep purple 
color so closely resembling the shade obtained with morphin that it can- 
not be used as a distinguishing test. Froehde's reagent produces no 
change at first, but a blue color gradually appears. Vanadium-sulphuric 
acid gives a green, and then gradually a blue color. Sulphuric acid con- 
taining ammonium selenite gives a green color; ammonium persulphate 
in sulphuric acid, orange. 

Pure codein does not reduce iodic acid; its solution does not give a 
blue color with a solution of ferric chloride, nor a blue precipitate with 
the latter and potassium ferricyanide. 

When dissolved in concentrated sulphuric acid and treated with a drop 
of 10 per cent sugar solution, a violet-red color appears which changes 
rapidly to deep red on heating over a water-bath. 

Codein picrate, prepared by precipitation from hydrochloric acid solu- 
tion and recrystallized from 10 per cent acetic acid, melts 195.5-196° C. 

Codein may be prepared synthetically from morphin, and may be 
considered a methyl derivative. 

Pseudomorphin 

Pseudomorphin sometimes occurs in opium, and may be prepared by 
the mild oxidation of morphin. In composition it may be considered as 
a product resulting from the condensation of two molecules of morphin 
with the loss of two atoms of hydrogen. It crystallizes in leaflets con- 
taining 3H2O, which decompose without melting. It is soluble in alkalies 
and ammonia, but insoluble in water, acids, alcohol, or ether. It is a 
non-poisonous weak base. It contains four hydroxyl groups and gives 
a tetra-acetyl derivative. 

Pseudomorphin will be of little concern to the drug analyst unless he 
becomes involved in a toxicological case where there is a question of its 
formation in the body as a condensation product of morphin. Its color 
reactions have been only imperfectly described. Hesse states that it gives 
a green color changing gradually to brown with sulphuric acid and sugar, 
and a blue to green with sulphuric acid containing a trace of iron. 



m 



ALKALOIDS DERIVED FROM ISOQUINOLIN 193 

Papaverin 
H H 

c c 

H 3 CO— C C CH 

! II I 

H3CO— C C N 

c c 

H I 

CH 

I 

C 

•\ 

HC CH 

I I 
HC C— OCH3 



C 

I 
OCH3 

The so-called papaverin group of the opium alkaloids includes most 
of the bases other than those previously described. They are all related 
to each other constitutionally and their structural groupings have, in 
some instances, been definitely established. Papaverin, narcotin, and 
narcein are the three most important and are the individuals with which the 
drug analyst may at times become concerned. They are all derivatives 
of isoquinolin, and their basic character is weak, standing thus in sharp 
contrast to morphin, codein, and thebain. 

Papaverin crystallizes in prisms or needles, melting 146-147°. It is 
inactive to polarized light. It is insoluble in water and alkalies, but dis- 
solves readily in hot alcohol, chloroform, benzol, and hot petroleum ether, 
and is somewhat soluble in ether. It is easily removed from an acidulated 
solution by chloroform and partially by ether. Narcotin is also removed 
from an acid solution by chloroform, and may be separated from papaverin 
by dissolving in oxalic acid and concentrating until the sparingly soluble 
acid oxalate of papaverin crystallizes out. Papaverin forms a very insolu- 
ble benzoate. 

This base gives with strong acids and oxidizing agents some well- 
marked color tests which are distinct from the colors given by narcotin 
and narcein, though it may be stated at this point that variations in color 
given by the latter may be due to the impurities present of which papaver- 
amin and cryptopin are of especial moment. It dissolves in concentrated 
sulphuric acid to a colorless solution, becoming violet on heating. 
Froehde's reagent gives a purple, gradually changing to blue; sulphuric 



194 ALKALOIDAL DRUGS 

acid and bichromate purple, turning brown and then changing back to 
purple; formaldehyde-sulphuric acid purple changing to crimson; and 
ammonium vanadate in sulphuric acid purple, blue, green and finally deep 
blue. It dissolves in nitric acid to a yellow solution. Narcotin gives a 
purple color with formaldehyde-sulphuric acid which turns to slate and 
soon fades, but gives no purple tint with any of the other reagents above 
mentioned. Narcein gives no purple color with any of them. Ammo- 
nium persulphate in sulphuric gives yellow with papaverin. 

On mixing papaverin ferricyanide with formaldehyde-sulphuric acid, 
a light-blue color is produced, soon changing to violet and finally green, 
the color then fading to brownish yellow. A similar change of colors 
results when papaverin and potassium ferricyanide are mixed in the dry 
state, and treated with formaldehyde-sulphuric acid. Warren *, who 
first reported this reaction, subjected a number of alkaloids to this 
test and found that, with the exception of an uncertain base from San- 
guinaria, none gave a reaction like papaverin. However, if selenious acid 
be used as the oxidizing agent, the initial color produced by the Sangui- 
naria base is an intense purple, while papaverin when thus treated gives 
a fugitive greenish blue which becomes deep blue. Warren found that 
a mixture of potassium permanganate and papaverin treated with for- 
maldehyde-sulphuric acid gave a green color, almost instantly changing 
to blue, then deepening into an intense violet-blue which after some time 
becomes bluish green, then green and finally dirty brown. 

Mullikin states that the pure base prepared from the oxalate which 
has been repeatedly crystallized gives no color reactions with concen- 
trated sulphuric acid, Froehde's, Mandelin's or Erdmann's reagents, and 
that with formaldehyde-sulphuric acid, the color is a faint pink chang- 
ing to brown. He claims that the color reactions given by commercial 
papaverin are due to the presence of cryptopin. 

Papaverin gives precipitates with several of the alkaloidal precipi- 
tating agents, but in dilute solutions none with phospho-molybdic acid, 
and is not thrown down by potassium-cadmium iodide. An alcoholic 
solution of iodin added to an alcoholic solution of papaverin gives a crys- 
talline precipitate on standing; this precipitate is decomposed by alkalies 
and ammonia. It forms a very sparingly soluble ferricyanide and acid 
oxalate. The picrate melts 179-181°, and the picrolonate 220° C. 

When oxidized with permanganate, papaverin yields a large number 
of well-defined compounds, among them being a body to which the name 
of papaveraldin has been given. Its composition is C20H19NO5, melting 
at 210°, and it differs from papaverin in possessing one more oxygen and 
two less hydrogen atoms. It is apparently identical with xanthalin. 
It reacts with hydroxylamin and phenylhydrazine, and when fused with 
1 J. Amer. Chem. Soc, 27, 1915, 2402. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 195 

alkalies is decomposed into veratric acid and dimethoxyisoquinolin. 
Another product of oxidation is papaveric acid, C16H13NO7, melting 233°. 
It is a dibasic acid containing a ketone group and on fusion with alkalies 
is converted to protocatechuic acid. Veratric and protocatechuic acids 
are among the final products of the direct fusion of papaverin with caustic 
alkalies. 

Hesse 1 has called attention to the fact that some of the samples of 
papaverin which he obtained had a percentage of carbon slightly above 
the normal even though he subjected them to repeated purification. The 
composition corresponded to C21H21NO4, and the alkaloid appeared to 
be more soluble in cold alcohol than was pure papaverin. Hesse has given 
the substance the name pseudopapaverin and believes that in some sea- 
sons it predominates while in others the normal form is obtained only. 

The complete synthesis of papaverin has been accomplished by Pictet 
and Gams. 

Papaveramin 

This alkaloid crystallizes in prisms melting at 128-129°; sightly soluble 
in water, alkalies, ether, and benzol, readily soluble in alcohol and chloro- 
form. It is of interest especially as an impurity of papaverin, which it 
follows very closely in its solubilities and other properties, and is probably 
the constituent of crude papaverin which causes violet-blue color with con- 
centrated sulphuric acid. 

Xanthalin 

This base is identical with papaveraldin, a product of the oxidation 
of papaverin with permanganate. It has been isolated from opium, 
though it is possible that it is formed from papaverin during the process 
of extraction. It is a crystalline powder, melting 2 08°, insoluble in water 
and alkalies, slightly soluble in alcohol and readily soluble in chloroform. 
Its salts have a yellow color. 

Laudain, Laudanidin, Laudanosin, Tritopin and Codamin 

These alkaloids are all closely related and are strong poisonous bases. 
The composition of laudanosin has been established as dextro-n-methyl- 
tetrahydropapaverin, laudanin is n-methyl-trimethylpaperverolin, and 
laudanidin is probably its lsevo modification. 

1 Laudanin crystallizes from alcohol or chloroform in prisms, inactive 
to polarized light, melting at 166°, readily soluble in alcohol and ether. 
It contains a phenolic hydroxyl and a neutral solution of its salts gives 
a green color with ferric chloride. With pure sulphuric acid it gives a 

J. prakt. Chem., 1903, 68, 190. 



196 ALKALOIDAL DRUGS 

faint pink tint, deepening if a trace of iron is present and turning to violet 
on heating. Nitric acid produces an orange-red color. 

Laudanin is not removed by chloroform from its solution in alkali 
hydroxides, but on adding ammonia the base is precipitated and may 
then be extracted. It forms a sparingly soluble hydriodide. When 
treated with methyl iodide in alkaline methyl alcohol, laudanin gives 
laudanin-methyl chloride and laudanin-methyl ester which is identical with 
z-laudanosin obtained from papaverin. 

Laudanidin closely resembles the former alkaloid, but is lsevorotatory 
and melts 177°. It may be separated from laudanin by means of its hydro- 
chloride, which is readily soluble in water; the hydrochloride of laudanin 
separates out from hydrochloric acid solution, especially if sodium chlo- 
ride is present to accelerate the precipitation. Its salts other than the 
hydrochloride closely resemble those of laudanin. 

Laudanosin crystallizes in needles, melting at 89°, soluble in alcohol, 
ether, chloroform, and benzol, and insoluble in water and alkalies. It 
is dextrorotatory. It gives no color with ferric chloride, and with sul- 
phuric acid alone and with oxidizing agents the reactions are similar 
to those given by laudanin. It gives a sparingly soluble hydriodide which 
serves as a very satisfactory means of separation. iV-methyl-tetra-hydro- 
papaverin, prepared synthetically, is identical in its chemical properties 
with laudanosin. It is a racemic body and may be separated into its 
constituents by quinic acid, the ^-compound being much less soluble in 
alcohol; the d-body is identical with natural laudanosin. 

Tritopin crystallizes in prisms from alcohol or in plates from ether, 
melting 182°. It is easily soluble in alkalies but is reprecipitated on add- 
ing excess of the reagent. It dissolves readily in chloroform and slightly 
in ether. Its color reactions with sulphuric acid are similar to those of 
laudanin. 

Codamin 

Codamin is a strong base, melting 121-126°, readily soluble in the ordi- 
nary solvents and alkalies and somewhat soluble in water. It gives a deep- 
green color with nitric acid and a greenish blue with sulphuric acid con- 
taining a trace of ferric chloride. 

Both laudanin and laudanidin are isomeric with codamin. 

Meconidin 

Meconidin is a strong base which occurs as a brownish-yellow amor- 
phous mass becoming liquid at about 58°. It is insoluble in water, but 
dissolves readily in alkalies and in the ordinary organic solvents. It is 
not removed from its solution in caustic alkalies by ether, but is shaken 
out of ammoniacal solutions with readiness. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 197 

Lanthopin 

Lanthopin is another of the minor alkaloids of opium and a weak 
base, soluble in alkalies, chloroform, ether, benzol, and alcohol, melting 
about 200°. It gives a colorless solution with sulphuric acid, darkening 
on warming, and an orange-red solution with nitric acid. It gives no 
color reaction with ferric chloride. 

Thebain 

Thebain is a very poisonous, strong, tertiary base, which, as we have 
already observed, is closely related structurally to morphin and codein. 
It contains no hydroxy 1 group, and is unaffected by acetyl chloride or 
phosphorus pentachloride. It crystallizes from alcohol in leaflets, melt- 
ing at 193 °, and is readily soluble in alcohol, ether, chloroform, and ben- 
zol, almost insoluble in water and alkalies, and insoluble in petroleum 
ether. In the regular scheme of analysis it will occur in the fraction 
obtained by shaking out the ammoniacal solution with ether. When heated 
to 130° it sublimes in caffein-like needles. Narcotin, narcein, and papa- 
verin do not sublime. 

Thebain differs markedly from codein and morphin in its color react- 
ions, giving a yellow with nitric acid and a red or reddish brown with 
sulphuric acid, Froehde's reagent, ammonium vanadate, and formalde- 
hyde-sulphuric acid. It is precipitated from an aqueous solution of opium 
by sodium salicylate, which forms a veiy sparingly soluble thebain 
salicylate. 

Dilute acids convert thebain into an amorphous base, thebanin, 
C18H19NO3, which is sparingly soluble in hot alcohol, and insoluble in 
the other ordinary organic solvents. 

The picrate, prepared as described under codein, melts 189-191° C. 

Protopin 

This is one of the minor alkaloids of opium, though it occurs in greater 
amounts in other drugs. It is of special interest from the fact that it 
is one of the few opium alkaloids that is not confined to that drug alone, 
but is quite widely distributed, being found in the root of Sanguinaria 
canadensis, Adlumia cirrhosa, Stylophorum diphyllum, Macleya cordata, 
and several species of Chelidonium and Corydalis. It is a strong nar- 
cotic base, crystallizing in needles from ether and chloroform, melting 
202° (207° Mullikin), insoluble in water and fixed alkalies, slightly solu- 
ble in alcohol, ether, and benzol, but dissolving in ammonia and readily 
in chloroform. It gives a yellow to red color with sulphuric acid, and a 
deep violet with sulphuric acid containing iron oxide. It gives no color 
with ferric chloride. Mullikin states that the color with concentrated 
sulphuric acid is blue-violet changing to muddy violet with a green mar- 



198 ALKALOIDAL DRUGS 

gin. Erdmann's reagent gives, according to the same authority, yellow, 
blue-violet, blue, green and yellow. 

It forms an amorphous aurochloride melting 198° C. 

Protopin appears to be identical with fumarin and macleyin. 

Cryptopin 

Cryptopin crystallizes from alcohol or ether in prisms, melting 213- 
218°. It is insoluble in water, alkalies, and ammonia, slightly so in ether, 
alcohol, and benzol, but dissolves readily in chloroform. It is a strong 
base and possesses hypnotic and mydriatic properties. With sulphuric 
acid it gives a violet color, changing to green and yellow, and if the acid 
contains iron oxide the color is deep violet. It occurs as an impurity in 
papaverin and is probably responsible for some of the color reactions 
attributed to its host. 

Erdmann's reagent gives a violet pink, changing to gray and yellow; 
Froehde's reagent, violet changing to blue-green, green and after some 
time yellow; formaldehyde-sulphuric acid, violet changing to brown. 

Salts of cryptopin, when dissolved in water, usually produce a gelatin- 
ous mass on cooling, and on standing the mass becomes crystalline. The 
picrate melts 215°. 

Cryptopin is closely related to protopin. It contains two methoxyl 
groups. 

Narcotin 

OCH3 
I 

c 

•\ 

HC C-OCHs 

I II 
HC CCO 

\/ 

c 

I 

HC— 

I 
CH3OC CH 

•\/\ 

/O— C C N-CH 3 

H 2 C<( I I I 

x O— C C CH 2 

c c 

H H 2 

Narcotin occurs in opium in varying amounts averaging about 5 per 
cent, and is one of the bases of this group, which may often prove of 
interest to the drug analyst. It is a weak base and probably exists in 



ALKALOIDS DERIVED FROM ISOQUINOLIN 199 

the free state in the drug, from which it may be removed by simple extrac- 
tion with ether. De-narcotized opium is a well-known article of commerce. 
Narcotin resembles papaverin and narcein by being extracted from acid 
solutions by chloroform; with papaverin it may be separated from nar- 
cein by precipitation with sodium acetate, and subsequently separated 
from papaverin by precipitating the latter with potassium ferricyanide. 

It crystallizes from alcohol or ether in prisms melting 176°, insoluble 
in cold water and cold alkalies, slightly soluble in hot water and petroleum 
ether, somewhat soluble in alcohol and ether and readily soluble in chloro- 
form and benzol. Its neutral solutions are lsevorotatory and its acid solu- 
tions dextro. 

Narcotin is precipitated by the general alkaloidal reagents. A solu- 
tion of the alkaloid in dilute hydrochloric acid gives a yellow T precipitate 
with bromin which dissolves on boiling. If bromin water is gradually 
added and boiled a rose color is produced and destroyed by excess of bro- 
min. A solution of the alkaloid in very dilute hydrochloric acid gives 
a white precipitate with potassium thiocyanate. 

If narcotin is heated with water at 140° or with sulphuric acid or barium 
hydroxide, it adds a molecule of water and is decomposed into opianic 
acid and hydrocotarnine. The opianic acid can then be recognized by 
the colorations produced with phenolic bodies. The test may be per- 
formed according to Labat 1 by dissolving .1 gram of the alkaloid in 0.5 
mil of 10 per cent sulphuric acid and gently heating, after the addition 
of 2 mils of a 2 per cent solution of potassium permanganate, until the 
pink color has disappeared. The liquid is then diluted with alcohol until 
the opianic acid is approximately 1 per cent, and the solution used for 
the tests. On mixing 0.1 mil of this solution with 2 mils of concentrated 
sulphuric acid and 0.1 mil of the phenolic solution the following reactions 
are obtained: with 5 per cent alcoholic solution of gallic acid, a blue color- 
ation rapidly appears changing to greenish brown; with a 5 per cent alco- 
holic solution of guaiacol or pyrocatechol gooseberry-red, changing to an 
intense blue when heated on the water-bath; with a-naphthol a goose- 
berry-red and with /3-naphthol a wine red. Hydrastin will, of course, 
give the same reactions as it also is converted to opianic acid under similar 
conditions. 

If 0.1 mil of an alcoholic solution of narcotin (1-100) is added to 2 
mils of concentrated sulphuric acid, 0.1 mil of 5 per cent solution of gallic 
acid added and the tube heated in a water-bath, an intense emerald-green 
color is obtained, changing to bright blue. This reaction is also given by 
hydrastin and hydrastinin. 

Zinc and hydrochloric acid, or sodium amalgam, reduce narcotin to 
meconin and hydrocotarnin. 

1 Bull. Soc. Chim., 1909, IV, 5, 743. 



200 ALKALOIDAL DRUGS 

Narcotin dissolves in sulphuric acid, yielding a pale-yellow solution, 
pink on the edges, and a red color gradually develops. Nitric acid or 
sodium hypochlorite added to its solution in sulphuric acid produce a 
red or carmine, and ferric chloride a cherry red. It gives a deep yellow 
with concentrated nitric acid, a deep green with Froehde's reagent; a 
brick-red with vanadium-sulphuric acid; and a purple to slate, soon fad- 
ing, with formaldehyde -sulphuric acid. Ammonium persulphate in sul- 
phuric acid gives orange red. 

Narcotin salts are not very stable, and water is usually sufficient to 
effect their decomposition. The hydrochloride and sulphate give clear 
solutions even when considerably diluted, but on adding sodium acetate 
to a solution of the hydrochloride the base is precipitated. The picrate 
melts 141° C. 

Narcotin is converted to narcein by digesting for ten hours with excess 
of methyl iodide, removing the excess of the latter on the water-bath, 
dissolving the residue in alcohol and treating with chlorin water. A 
light-yellow precipitate is first formed, which soon dissolves; with excess 
of chlorin the precipitate is darker, and after standing a few hours becomes 
crystalline. The filtrate on evaporation yields a brownish gum, becom- 
ing crystalline narcotin methylchloride, which gives narcein by neutraliz- 
ing with sodium hydroxide and passing a current of steam. 

Gnoscopin 

This alkaloid has been shown by Perkin and Robinson x to be racemic 
narcotin. It may be prepared from narcotin by heating with acetic acid 
to 130°, or by boiling cotarnin and meconin with potassium carbonate 
in alcohol. It melts at 228-233°, is insoluble in water and alkalies, slightly 
soluble in alcohol, and readily soluble in chloroform and benzol. It dis- 
solves in sulphuric acid to a yellow solution, becoming red on the addition 
of nitric acid, the color being permanent. The picrate melts 200° C. 

Oxynarcotin 

This is a feeble base which occurs in crude narcotin. It is slightly / 
soluble in alcohol and hot water and insoluble in the ordinary alkaloidal 
solvents. 

Hydrocotarnin 

This alkaloid was found in opium by Hesse. It is formed by the decom- 
position of narcotin and crystallizes in prisms containing one-half mole- 
cule of water, melting at 55°. It is insoluble in water and alkalies but 
dissolves in organic solvents. It may be distilled with little decompo- 
1 Proc. Chem. Soc, 1910, 26, 46, 131. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 201 

sition at about 100° C. It is a tertiary base and a derivative of methyl- 
tetrahydroquinolin. By the action of sulphuric acid it forms a conden- 
sation product, hydro dicotarnin, C24H28N2O6. 

Hydrocotarnin dissolves in concentrated sulphuric acid with a yellow 
color, changing to carmine, blue-violet, and violet on warming. 

Narcein 

OCH3 
6 



HC COCH3 

I II 
HC C-COOH 

V 

c 

I 
CH30 9° 

C CH 2 
/\/ ,CH 3 
/O-C C N< 

H 2 C< | II IXJHa 
x OC C CH 2 

c c 

H H 2 

Narcein has apparently the weakest basic properties of the opium 
alkaloids and has distinct acid properties. It contains a carboxyl and 
a carbonyl group, forms definite compounds with potassium and sodium 
hydroxide and reacts with hydroxylamine and phenyl hydrazine. 

Narcein crystallizes from water or alcohol in prismatic needles con- 
taining 3 molecules of water, optically inactive, melting 170-171°. The 
water is all driven off on heating to 100° and the anhydrous base melts 
at 145°. As prepared commercially it is separated with difficulty from 
the acid radicle, even when precipitated in presence of free ammonia, and 
hence its melting-point is variable. It is slightly soluble in cold water 
and chloroform, readily soluble in hot water, alkalies, and alcohol, and 
insoluble in ether, benzol, and petroleum ether. It is partly removed 
from a cold acidulated solution by chloroform, but the extraction is not 
complete and it is carried along in the aqueous liquid through the shake- 
outs in alkaline solution until it is finally found in the alcohol-chloroform 
fraction with morphin. 

Narcein gives no precipitate with Mayer's reagent, mercuric chloride, 
or potassium ferrocyanide ; it is precipitated by gold and platinic chlo- 
rides, picric acid, tannin and by potassium bichromate on standing. With 



202 ALKALOIDAL DRUGS 

iodin a brown precipitate is obtained, and on removing the excess of 
iodin by ammonia, the precipitate is found to be blue. Weak iodin 
solutions color narcein a dark blue; on dissolving in boiling water a color- 
less solution results from which violet or blue crystals separate on cooling. 
If iodin is strewn on a cold saturated solution of narcein, fine needle- 
like gray crystals form around the iodin. The picrate melts 127-128.5° 
and the platinochloride begins to darken at 190° and melts 198-199° C. 

Narcein forms crystalline salts with caustic alkalies by heating the 
base at 60-70° with a 33 per cent solution of the alkali. The alkaloid is 
regenerated when the salts are treated with acids or carbon dioxide. 

The color reactions of narcein are not especially characteristic; with 
sulphuric acid it gives a brown color, becoming yellow, green, and finally 
blue; Froehde's reagent gives greenish brown, vanadium sulphuric acid 
reddish brown; formaldehyde-sulphuric acid, brown, greenish on edges; 
nitric acid a fading yellow. When treated with sulphuric acid contain- 
ing a trace of tannin a green color is produced, the same reaction being 
given by narcotin and hydrastin. When warmed with sulphuric acid 
containing a trace of resorcinol, a crimson to cherry-red color is produced, 
becoming blood-red on cooling and gradually fading to orange. Ammon- 
ium persulphate in sulphuric acid gives violet changing to blood-red and 
yellow. 

A solution of narcein in very dilute hydrochloric acid gives a precipi- 
tate of white hair-like crystals becoming blue on standing, with a few 
drops of potassium-zinc iodide solution. 

0.01 gram narcein in 5 mils of very dilute hydrochloric acid gives an 
orange-red coloration with 1 mil of chlorine water, followed by an excess 
of ammonia. Thebain under similar conditions gives a reddish-brown 
color. 

Ethyl narcein hydrochloride is known as narcyl, and occurs in pris- 
matic needles soluble in water and alcohol. 

Apomorphin 

This body was mentioned under the description of morphin as being 
one of its alteration products, differing from the parent substance by the 
elements of one molecule of w T ater, and being the characteristic substance 
produced in performing Pellagri's test. It occurs on the market as the 
crystalline hydrochloride and is generally employed as an emetic, expector- 
ant, or hypnotic in the form of syrups and hypodermatic tablets. It is 
a substance which is very prone to decompose and furthermore often con- 
tains impurities. It is seldom administered with other drugs. 

The base itself, when freshly precipitated, is white and amorphous, 
but it soon turns green on exposure to light and air. It is readily soluble 



ALKALOIDS DERIVED FROM ISOQUINOLIN 203 

in alcohol, ether, chloroform, and benzol; the solutions taking various 
shades of green, magenta, or violet. In the regular scheme of analysis, 
apomorphin will first make itself apparent when ammonia is added to 
the acid solution preparatory to shaking out with petroleum ether; at 
this juncture a green color appears, becoming more or less deep and intense, 
depending on the quantity of the base present; on shaking out with ether 
the solvent will acquire a magenta shade, due to the removal of some of 
the oxidation products. The same reaction will be obtained on shaking 
with either chloroform or benzol, the shades often varying from magenta 
to violet or purple. 

These reactions are about all that is necessary to diagnose the pres- 
ence of apomorphin. Pilocarpin gives oxidation products which dis- 
solve in volatile solvents with bluish shades, but these oxidation products 
require for their production the assistance of some agent stronger than 
atmospheric oxygen, and hence are not formed in the ordinary procedure 
of analysis. 

The color reactions given by apomorphin residues with the oxidizing 
agents used in the detection of the opium alkaloids are as follows : nitric 
acid gives at first a violet color soon changing to mahogany brown and 
later to orange; Froehde's reagent gives a deep blue, fading to slaty 
violet; vanadium-sulphuric acid a deep blue; formaldehyde-sulphuric 
acid a purple with a greenish-blue cast underneath, finally deep blue- 
black; bichromate and sulphuric acid deep green. 

Apomorphin solutions, even when extremely dilute, give a green color- 
ation when rendered faintly alkaline with potassium bicarbonaate. If 
a dilute solution is made alkaline with sodium hydroxide, a few drops of 
chloroform added and the mixture shaken, the chloroform will settle out 
with a blue color and the aqueous layer will be violet. With ferric chloride 
a rose-red color is obtained changing to violet and black. With a dilute 
solution of ferrous sulphate the solution becomes blue and then black, 
returning to blue on adding alcohol. Iodic acid gives the same color- 
ation as is obtained with a solution of morphin. 

The hydrochloride occurs in the amorphous state and in minute crys- 
tals, the latter form being the purest. The crystals should be kept tightly 
corked and away from the light and a freshly made solution should be 
colorless or with but a slight green color. Some commercial hydrochlo- 
rides have been found to contain varying amounts of beta-chloromor- 
phide which may be detected by dissolving 0.1 gram in 10 mils of water, 
adding 5 mils of saturated sodium-carbonate solution, shaking with ether, 
washing the ether with 3 portions of water, and then evaporating the 
ether. The ether residue is then treated with 5 mils of concentrated 
nitric acid and .02 gram silver nitrate, and after standing a short time is 
heated on the steam-bath, water being added from time to time to keep 



\ 



204 ALKALOIDAL DRUGS 

up the volume. If any appreciable amount of silver chloride is seen, 
the presence of the impurity is indicated. 

If potassium ferricyanide is added to a dilute solution of apomorphin 
followed by benzol and shaking, the solvent will be colored an amethyst 
violet changing to violet red on shaking with sodium hydroxide. 

The free base precipitated from hydrochloric acid solution by sodium 
bicarbonate, melts 160-170° with decomposition. The melting-point 
constant is not very reliable, because of the difficulty of obtaining a pure 
product free from oxidation products. 

Apomorphin methyl bromide, C17H17NO2 • CHsBr, known as eupor- 
phin, occurs in the form of colorless needles or scales, melting 180° C, 
and readily soluble in water and alcohol. It is used for the same pur- 
poses as apomorphin and its solutions seem to be more stable. 

Apocodein 

Apocodein, which is prepared from codein in an analogous way to 
apomorphin from morphin, is probably an indefinite mixture of basic 
derivatives of codein and morphin. It has a limited use as the hydro- 
chloride, which is a yellowish to greenish-gray hygroscopic powder. The 
base gives a blood-red color with nitric acid; with Froehde's reagent a 
blue changing to brown and green to a purplish olive; with formalde- 
hyde-sulphuric acid a brown to brownish purple, then black. 

Eucodein 

Codein methyl bromide occurs in colorless crystals, melting at 261°, 
readily soluble in water and slightly in alcohol. It is soluble in sulphuric 
acid with evolution of hydrobromic acid, gives a brown-violet to blackish- 
green color with formaldehyde-sulphuric acid, and a brown to dirty green 
with Froehde's reagent. 

Heroin, Diacetyl morphin, C21H23NO5 

Heroin is probably the most widely used artificial derivative of mor- 
phin and is readily prepared from its parent base by heating with acetyl 
chloride or acetic anhydride. The diacetyl morphin is liberated by a 
mild alkali and extracted in the cold and may be crystallized out of alcohol. 
The free base melts 171-172°, is almost insoluble in water and petroleum 
ether, somewhat soluble in alcohol and ether, and readily soluble in chloro- 
form and benzol. When heated in solution it is prone to decompose and 
in analytical work the manipulations must be done in the presence of 
ice. This factor must be considered in quantitative work when one is 
working with a product in which a stated amount of heroin has been 
declared. If a smaller quantity than that declared is found, it must not 



ALKALOIDS DERIVED FROM ISOQUINOLIN 205 

be considered conclusive that the proper quantity was not originally 
present, but a further examination must be made for morphin. 

It differs from morphin in being completely and easily removed from 
alkaline solutions by chloroform and in giving a pale-yellow color grad- 
ally turning green with nitric acid. It gives a brilliant crimson-purple 
color, soon fading, with Froehde's reagent, a permanent crimson-purple 
with formaldehyde-sulphuric acid; and a pale violet soon fading with 
vanadium-sulphuric acid. With hexametlrylene tetramine in sulphuric 
acid a golden-yellow color is obtained, changing to saffron and finally 
to blue. 

On heating with sulphuric acid and alcohol, ethyl acetate is formed, 
which becomes apparent by its odor. 

Its neutral solutions do not liberate iodin from iodic acid, nor give 
a blue color with ferric chloride. It is precipitated by the ordinary alka- 
loidal reagents. The picrate, recrystallized from 50 per cent alcohol, melts 
200-205° C. 

Heroin is a cough sedative and antispasmodic, and is used in remedies 
for consumption, asthma, bronchitis, and similar ailments. The hydro- 
chloride is a white crystalline powder readily soluble in water and alcohol. 

Ethyl morphin, Ci 7 His(C 2 H 3 )N0 3 

Ethyl morphin, the base of Dionin, which is its hydrochloride, is 
closely related to codein and resembles the latter in its properties. It 
is liberated from its acid solution by alkalies and may be completely 
removed from alkaline solution by ether and chloroform, but it is insolu- 
ble in petroleum ether. When heated to 110-115° it decomposes with- 
out melting. It gives a yellow color with nitric acid; a green to deep 
green and eventually a blue color with Froehde's reagent differing to some 
extent from codein in the first phase of this reaction ; purple with formal- 
dehyde-sulphuric acid; and green with vanadium-sulphuric acid. It is 
less soluble in ammonia than codein, a 10 per cent solution of the hydro- 
chloride of the latter gives a precipitate on the addition of a few drops 
of ammonia soluble on the addition of 1 mil excess, while with a 10 per 
cent solution of dionin, the separated base does not go into solution until 
5 mils of ammonia are added, and soon separates again on standing. 

The hydrochloride, which is the form in which it is always found 
commercially, is a white crystalline powder, readily soluble in water and 
alcohol. A solution of the substance in water when added to ferric chlo- 
ride containing a trace of potassium ferricyanide develops a blue-green 
color. 



206 ALKALOIDAL DRUGS 

Benzyl Morphin, C 17 Hi 8 N0 2 OC 6 H 5 CH2 

Benzyl morphin is the base of Peronin, the commercial name of its 
hydrochloride. It is liberated from its acid solutions by alkalies and 
under these conditions may be shaken out partly by petroleum ether and 
readily by ether. The residue gives a yellow color with nitric acid, a 
brown, violet, brownish green to slate with Froehde's reagent; an olive 
brown with vanadium-sulphuric acid; and a crimson, with a purplish 
shade gradually appearing with formaldehyde-sulphuric acid. 

Meconic Acid 
O 

c 

/\ 

HC COH 

II II 
COOH— C C— COOH 

\y 

o 

From an analytical standpoint, meconic acid is the most important 
of the non-basic constituents of opium for its identity serves to substanti- 
ate the presence of the drug. In the ordinary scheme of qualitative 
analysis, the acid will appear in the ether shake-out from acid solution 
and will be indicated by the deep-red color it gives when its aqueous 
solution is treated with ferric chloride. The deep-red color is not dis- 
pelled on warming with hydrochloric acid nor changed by gold chloride, 
it is, however, bleached by stannous chloride and restored by potassium 
nitrite. It may be purified by precipitating in aqueous solution with 
lead acetate, washing the precipitate, subjecting the latter to a stream 
of hydrogen sulphide in the presence of water and after filtering from 
the lead sulphide the pure acid may be shaken out with ether. 

Meconic acid crystallizes in micaceous scales or rhombic prisms with 
3 molecules of water. It loses its water of crystallization at 100° and 
at 120° is converted to comenic acid, C6H4O5, with loss of CO2, and on 
further heating yields pyromeconic acid with a further loss of CO2. 

/OH /OH /OH 

C 5 H0 2 ^-COOH C 5 H0 2 f-H C 5 H0 2 ^-H 

\COOH \COOH NB 

Meconic Acid Comenic Acid Pyromeconic Acid 

Comenic acid is insoluble in cold water and absolute alcohol and spar- 
ingly soluble in boiling water. Both this acid and pyromeconic acid give 
red colorations with ferric chloride. 

Meconic acid is -fairly soluble in cold and readily in hot water, and is 
rendered less soluble by the presence of hydrochloric acid. It is readily 



ALKALOIDS DERIVED FROM ISOQUINOLIN 207 

soluble in alcohol and ether, and insoluble in chloroform. The solid acid 
gives a characteristic purple to deep blue color, gradually fading, with 
vanadium sulphuric acid. The microscopic appearance of its crystals 
from aqueous solution and of the precipitates with barium chloride, cal- 
cium chloride and potassium ferrocyanide are characteristic. 

Meconin is often an impurity in the meconic acid extraction from 
opium and may be separated and identified by shaking the solution with 
benzol or chloroform which removes the meconin leaving the meconic 
acid in solution. On evaporating the solvent the meconin residue may 
be treated with concentrated sulphuric acid which will give a pale yellow 
color gradually changing to pale violet on standing. On adding a frag- 
ment of potassium nitrate to a solution of meconin in concentrated sul- 
phuric acid, a yellow coloration is obtained, rapidly changing to scarlet. 

Meconin is a neutral substance, somewhat soluble in boiling water, 
and ether, and dissolving readily in alcohol, chloroform, and benzol. It 
crystallizes in prisms which melt under water at 77°. The crystals melt 
in the air at 102-103°. It is a reduction product of opianic acid and is 
produced when narcotin is treated with zinc and hydrochloric acid. Its 
formula is 

CH 2 — O 

K l 

-CO 
I— OCH3 



OCH3 

Qualitative and Quantitative Determination of the Opium Bases and 
Their Derivatives. — The alkaloids of this group are not difficult to detect 
and in the regular scheme of separation will appear in the several frac- 
tions where their identity will be indicated and from that point can be 
substantiated by applying the various reactions described for the specific 
individuals. As we have indicated in the preceding paragraphs, the num- 
ber of individuals of interest from an analytical standpoint is limited to 
morphin, codein, narcotin, papaverin, thebain, narcein, and meconic acid 
among the naturally occurring substances; and to heroin, ethylmorphin, 
and apomorphin in the artificial group. In quantitative work the analyst 
will seldom be called upon to determine other than morphin, codein, 
heroin, and ethylmorphin. Morphin is, in one way, about the easiest 
alkaloid to separate from other bases as it is not removed from its solu- 
tion in caustic alkalies by immiscible solvents, and from ammoniacal 
solutions with difficulty only with chloroform, and not with ether. 

In qualitative work, an alcoholic extract of the dry sample or of an 



208 ALKALOIDAL DRUGS 

evaporated liquid product should be concentrated to drive off the alcohol 
and then taken up with water and dilute sulphuric acid and subjected to 
the shaking-out scheme with immiscible solvents. Petroleum ether will 
remove nothing of interest of this group; ether will take out meconic 
acid, meconin, a little narcotin, and narcyl; chloroform will extract nar- 
cotin, papaverin, narcyl, and some of the narcein. The solution should 
then be rendered slightly alkaline with dilute potassium or sodium hydrox- 
ide and any green color noted which will at once indicate apomorphin; 
petroleum ether will take out some of the peronin if this substance is 
present; ether will remove apomorphin partly (both solvent and alkaline 
solution becoming colored, due to oxidation products), codein, ethyl- 
morphin, thebain, apocodein, and laudanosin will be completely extracted, 
heroin, papaverin, and laudanin in part; following this shake-out chloro- 
form will remove the rest of the apomorphin, heroin, laudanin, protopin, 
and a further quantity of papaverin if this has not been entirely removed 
in the previous fractions; morphin and narcein may then be shaken out 
by adding a little ammonium chloride and shaking out with chloroform- 
alcohol 2-1. 

After evaporating the solvents in the separate fractions, portions of 
each residue should be examined in the following order: the ether frac- 
tion from acid solution will give evidence of meconic acid by the ferric 
chloride and vanadium-sulphuric acid test and this body can be separated 
from meconin and the latter detected as described under meconic acid; 
narcotin will be indicated by the tests with Froehde's reagent, vanadium- 
sulphuric acid, and formaldehyde-sulphuric acid. The chloroform resi- 
due from acid solution will give indication of narcein, narcotin, and papav- 
erin by the color tests with sulphuric acid, Froehde's reagent, vanadium- 
sulphuric acid, formaldehyde-sulphuric acid, and nitric acid. In the 
petroleum ether residue from the alkaline solution peronin will be indi- 
cated by the tests with formaldehyde-sulphuric acid and Froehde's reagent. 
In the next residue, ether from alkaline solution, the greatest variety may 
occur; nitric acid will give green with heroin, yellow with codein, and 
violet to deep brown and finally orange with apomorphin; formaldehyde- 
sulphuric acid will give shades of reddish purple and violet with codein, 
heroin, ethylmorphin, peronin, papaverin, apomorphin, and apocodein and 
red-brown with thebain; Froehde's reagent will give blue with codein, 
green to blue with ethylmorphin, purple to blue with papaverin, crimson 
purple with heroin, blue to violet fading to brownish green and finally 
slate with peronin, and red-brown with thebain. The chloroform frac- 
tion in the main serves to substantiate the results obtained with the ether 
fraction and in the chloroform-alcohol fraction morphin will be indicated 
by its reactions with nitric acid, Froehde's reagent, and formaldehyde- 
sulphuric acid : narcein with sulphuric acid alone gives a deep-brown color 



ALKALOIDS DERIVED FROM ISOQUINOLIN 209 

at the moment of solution, this changes to yellow, then green, and finally 
blue. 

If one finds meconic acid, morphin and some of its associated alkaloids, 
he may feel reasonably certain that he is dealing with a product contain- 
ing opium. 

Kerbosch 1 describes a method of separating the opium alkaloids from 
each other. The mixed bases are extracted with a mixture of chloro- 
form-alcohol 4-1 containing a trace of ammonia, the solvent evaporated 
and the residue dissolved in N/10 hydrochloric acid, narcotin is then parti- 
ally precipitated by sodium acetate; sulphuric acid is added and papaverin 
thrown out by caesium cadmium iodide, the crystals being identified 
microscopically; narcein is then precipitated by sodium acetate and iden- 
tified by the blue coloration imparted with iodin; thebain is also precipi- 
tated in presence of sodium acetate. The solution is then thoroughly 
shaken out with chloroform, ammonia added, the codein removed by 
benzol and morphin by chloroform-ether mixture, both being identified 
by the characteristic forms of their csesium-cadmium-iodide compounds. 

Plugge has also given a scheme for separating the opium alkaloids 
which deserves consideration. A solution of the free alkaloids is treated 
with sodium acetate which precipitates the Earcotin and papaverin. The 
filtrate is set aside and the precipitate dissolved in the least quantity of hy- 
drochloric acid and diluted with water to a f-per cent solution, from which 
the papaverin is precipitated by potassium ferricyanide, and after filter- 
ing and adding ammonia, the narcotin is shaken out with chloroform. 
The filtrate from the sodium acetate precipitation is concentrated and 
the narcein will crystallize out; it is filtered, concentrated sodium salicy- 
late added and allowed to stand twenty-four hours for the thebain salicy- 
late to crystallize. It is then filtered, acidulated with hydrochloric acid, 
and the excess of salicylic acid and any traces of thebain and narcein 
removed with chloroform. The solution is then concentrated, potassium 
sulphocyanide added, which precipitates the codein, it is filtered, ammonia 
added, any residual codein removed by ether, then acidified, heated to 
60° C, ammonia added, and the morphin shaken out with chloroform- 
alcohol mixture. 

When it is necessary to look for these alkaloids in lozenges or medica^ 
ments containing large quantities of gum, the sample should be dissolved 
in water, employing as small a quantity as possible, a little acid added 
and the solution poured into about ten times its volume of alcohol. This 
will precipitate the gum which soon coagulates and settles to the bottom 
or collects on the sides of the container. The solution contains the alka- 
loids and it may be filtered, neutralized and the alcohol evaporated, the 
rest of the separation being conducted as usual. 

1 Arch. Pharm., 248, 1910, 536. 



210 ALKALOID AL DRUGS 

Opium alkaloids may be detected without difficulty when they occur 
in mixtures containing at the same time the bases of ipecac, Hyoscyamus, 
and cinchona, though the reverse is not accomplished with the same 
facility for the brilliant color tests of the opium bases obscure the reac- 
tions of the other substances. 

Atropin is readily identified when it occurs with morphin alone, for 
it is removed from alkaline solution by ether, leaving the morphin still 
in solution. The same condition prevails if strychnin, cocain, hydrastin, 
or Sanguinaria bases are present, they are all removed from an alkaline 
(caustic) solution by immiscible solvents, leaving the morphin. On sub- 
sequently adding ammonium chloride and shaking out with chloroform- 
alcohol mixture the morphin will be extracted. Acetanilid mixtures give 
up their acetanilid to chloroform in acid solution and caffein may be 
separated in like manner. 

Codein may be identified when in mixtures with acetanilid or caffein 
by first shaking out these two substances from acid solution with chloro- 
form. Colchicin may also be removed under the same conditions. Anti- 
pyrin cannot be satisfactorily separated from codein, but it may be identi- 
fied when present, for it is partly removed from acid solution while codein 
is not, and codein gives certain reactions to which antipyrin does not 
respond, Apomorphin, heroin, ethylmorphin, and benzylmorphin will 
probably seldom if ever be found in admixtures with other bases. 

Much attention has been given to the determination of morphin in 
opium products and many methods for accomplishing this purpose have 
appeared during the last ten years. Probably the greatest advance in 
evolving accurate, simple, and rapid methods has been attained at the 
Bureau of Chemistry of the U. S. Department of Agriculture and in 1909 
Eaton * published his method for the estimation of morphin in opium, 
paregoric, laudanum, and cough mixtures. The writer has tried the 
method on many occasions and has found it most easy of application and 
accurate in its results, but like many other procedures in alkaloidal anal- 
ysis it should not be attempted by a novice until he has familiarized him- 
self with all its details. Following this work Buchbinder made an exhaust- 
ive study along the Eaton line of research and has communicated to 
me a modification of Eaton's method which bids fair to settle the many 
difficulties which have attended this important subject. 

Eaton's method for the determination of morphin in opium was given 
in full on page 57. The adaptation of this procedure to opium prepa- 
rations is given at this point. 

i Bur. Chem. U. S. Dept. Agri. Bull. 137, p. 188. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 211 

ESTIMATION OF MORPHIN IN PAREGORIC 

Evaporate 100 mils on the water-bath to a volume not exceeding 15 
mils. Transfer to a separatory funnel, using no more than 2 or 3 mils of 
water at a time for the rinsings and no more than 15 mils in all. Shake 
out twice with 25 mils of ether, collect the ether and wash with 5 mils of 
water. Reject the ether and add the wash water to the main aqueous por- 
tion. To the latter add 30 mils of lime water, mix thoroughly, filter into 
a separatory funnel (No. 1), and wash with several small portions of lime 
water, using no more than 20 mils in all. 

Proceed as in the method given for opium, beginning with the fourth 
sentence: " Shake out seven times with washed chloroform," etc. 

ESTIMATION OF MORPHIN IN SYRUP PREPARATIONS 

Take a convenient volume to yield between 30 and 75 milligrams of 
morphin. Make acid, then ammoniacal, and extract to complete exhaus- 
tion with a mixture of chloroform and alcohol, using large proportions 
of alcohol than that given above, if necessary to clear emulsions. In 
all cases do not consider the morphin exhausted until an actual test with 
5 mils of the last shake-out, carried out as indicated above in the method 
for opium (Mayer's reagent), shows it to be free from alkaloid. Do not 
test before at least seven shake-outs (not including the last shake-out on 
a portion of which the test is to be carried out) have been made. Evapo- 
rate (on the water-bath) the combined chloroform-alcohol to dryness. 
Take up in 30 mils of lime water, filter into a separatoiy funnel, rinse, 
and wash several times with small portions of lime water, using about 
20 mils in all. 

Proceed as in the method for opium, beginning with the fourth sen- 
tence: " Shake out seven times with washed chloroform," etc. 

Mr. Buchbinder's method for the determination of morphin as com- 
municated to me is quoted herewith in full. 

POWDERED OPIUM 

Reagents : 

Sodium hydroxide, 10 per cent. 

Common salt. 

Alkaline salt solution, made by saturating a 2 to 2J per cent sodium 

hydroxide solution with common salt and filtering. 
Barium chloride, a saturated solution. 
Concentrated hydrochloric acid. 
Concentrated ammonia. 
Alcohol. 
Chloroform. 
Methyl red (.2 per cent alcoholic solution), or Cochineal. (IT. S. P.) 



212 ALKALOIDAL DRUGS 

Digest 2 grams of powdered opium in 50 mils of water in a loosely 
stoppered Erlenmeyer for twenty minutes at a temperature between 90 
to 100° C. While still hot add 20 mils of 10 per cent sodium hydroxide, 
and rotate gently. Allow to cool somewhat, stopper the Erlenmeyer and 
shake, not too violently, during ten minutes. Transfer the contents of 
the Erlenmeyer into a 200-mil graduated flask containing 18 to 20 grams 
of powdered common salt. Stopper and shake gently until the salt is 
dissolved. Rinse the Erlenmeyer and the stopper with several portions 
of alkaline salt solution, adding the rinsings to the graduated flask, and 
dilute with the same solution to a total volume of about 175 mils. Rotate 
so as to mix. Add 15 mils of a saturated solution of barium chloride. 
Reduce the froth by the addition of a little alcohol and make up to volume 
with alkaline salt solution. Stopper, shake thoroughly, then filter through 
a large, dry, fluted paper, if not clear, refilter. 

By means of a pipette remove 100 mils of the filtrate, corresponding 
to half the weight of the sample taken and introduce into a separatory 
funnel No. 1. Add concentrated hydrochloric acid in portions — towards 
the end not over J mil at a time — until acid to litmus; then add 4 mils 
in excess. Add concentrated ammonia in portions, — towards the end 
not over 4 drops at a time — until alkaline; then add 1 mil in excess. Add 
10 mils of alcohol and shake out six times with chloroform, 30, 20, 20, 
15, 15, and 15 mils respectively, filtering each successive shake-out through 
a piece of cotton wetted with chloroform and wedged in the neck of a 
small funnel, into a separatory funnel No. 2. Discard the liquid in separa- 
tory funnel No. 1. 

To funnel No. 2 add 15 mils of alkaline salt solution, shake, then with- 
draw the chloroform layer into a separatory funnel No. 3. To funnel 
No. 3 add 5 mils of alkaline salt solution, shake, withdraw the chloroform 
layer into a beaker and add the alkaline salt layer to funnel No. 2. Return 
the chloroform to funnel No. 3, shake with a fresh portion of 5 mils alka- 
line salt solution, reject the chloroform layer and keep the alkaline salt layer 
for later use. Shake out the alkaline salt solution in funnel No. 2 twice 
with 25 mils of chloroform each time, collecting the chloroform in a separa- 
tory funnel No. 3. Shake funnel No. 3. Reject the chloroform layer 
and add the alkaline salt layer to the main alkaline salt solution in funnel 
No. 2. 

To funnel No. 2 add concentrated hydrochloric acid carefully, reach- 
ing acidity within 2 or 3 drops; then add 1 mil in excess. Add concen- 
trated ammonia carefully, reaching alkalinity within 1 or 2 drops; then 
add 5 drops in excess. Add 3 mils of water and 4 mils of alcohol. Shake 
out five times with chloroform, 30, 10, 10, 5, and 5 mils respectively, 
filtering each successive shake-out through cotton wetted with chloro- 
form into a beaker. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 213 

Evaporate the chloroform on the water-bath to dryness. Add 10 to 
20 mils of neutral alcohol and heat to dissolve. Add 3 drops of methyl 
red or 5 drops of cochineal. Add N/50 sulphuric acid until about 2 to 
5 mils in excess. At this stage look out for any undissolved specks; heat 
again if necessaiy. If cochineal is used the alcohol should be almost 
entirely evaporated . If methyl red is used either evaporate the alcohol 
or else add water until a pure red tint is obtained. Titrate back with N/50 
or N/100 sodium or potassium hydroxid which has been ascertained to 
be sufficiently free from carbonates to give a sharp end point with the 
indicator used. 

One mil of N/50 acid corresponds to 6 mgms. of crystallized morphin. 
If more than 150 mgms. are indicated, repeat the analysis with a smaller 
quantity of the sample. 

GUM OPIUM 

Weigh out about 2 grams of gum opium in a beaker. Add 50 mils of 
water, cover with a watch glass and digest at a temperature between 90 
to 100° until thoroughly disintegrated. Use a glass rod to mash particles. 
Transfer to an Erlenmeyer and while still hot add several portions of 
10 per cent sodium hydroxide, using those same portions first to rinse 
the beaker, using in all about 20 mils. Allow to cool somewhat, stopper 
the Erlenmeyer and shake not too violently during ten minutes. Trans- 
fer the contents of the Erlenmeyer into a 200-mil graduated flask con- 
taining 18 to 20 grams of powdered common salt. Stopper and shake 
gently until the salt is dissolved. Rinse the Erlenmeyer and the stopper 
and also the beaker in which the digestion of the opium was made, with 
several portions of alkaline salt solution, adding the rinsings to the gradu- 
ated flask, and dilute with the same solution to about 175 mils. Proceed 
as directed for opium, beginning with the seventh sentence in the first 
paragraph: " Rotate so as to mix." 

LAUDANUM 

Into a beaker to which has been added 40 mils of water and 20 mils of 
10 per cent sodium hydroxide, introduce from a pipette or a burette 20 
mils of laudanum. Stir with a glass rod, then transfer into a 200-mil 
graduated flask containing 18 to 20 grams of powdered common salt. 
Stopper and shake gently until the salt is dissolved. Rinse the beaker 
with several portions of alkaline salt solution, adding the rinsings to 
the graduated flask, and dilute with the same solution to a volume of 
about 175 mils. v Proceed as directed for powdered opium, beginning with 
the seventh sentence in the first paragraph: " Rotate so as to mix." 



214 ALKALOIDAL DRUGS 

PAREGORIC 

Evaporate 200 mils of the sample to a volume of 50 or 60 mils. Trans- 
fer to a separatory funnel, rinsing the vessel in which the evaporation 
was made with several small portions of water, adding the rinsings to 
the separatory funnel. Shake out three times, 20 mils each time, with 
ether, collecting the ether in another separatory funnel. Wash the ether 
with 5 mils of water. Reject the ether and add the wash water to the 
main aqueous layer. Withdraw the latter into a beaker, rinse the funnel 
with several small portions of water, adding the rinsings to the beaker. 
Heat the beaker on the water-bath until all the ether is expelled. Add 20 
mils of 10 per cent sodium hydroxid. Rotate so as to mix. Transfer 
into a 200-mil graduated flask containing 1 gram of powdered common 
salt for every 3 mils of the solution. Add 15 mils of water. Stopper 
the flask and shake gently until the salt is dissolved. Rinse the beaker 
with several portions of alkaline salt solution, adding the rinsings to the 
graduated flask, and dilute with the same solution to about 175 mils. 
Proceed as directed for powdered opium, beginning the seventh sentence 
in the first paragraph; " Rotate so as to mix." 

THE DETERMINATION OF MORPHIN IN TABLET TRITURATES. DIRECT 
EXTRACTION METHOD, H. E. BUCHBINDER 

Reagents : 

Sodium chloride — finely powdered. 
Ammonium chloride. 
95 per cent alcohol. 
Cone, ammonia — 25 to 28 per cent. 
Chloroform. 

Neutral 95 per cent alcohol for dissolving the alkaloidal residue; 
10 mils diluted with 20 mils of water to which has been added 
3 drops of methyl red, should not require more then one drop 
of N/50 alkali to turn yellow. 
Methyl Red — a 0.2 per cent alcoholic solution. 
Standard N/50 sulphuric acid. 

Standard N/50 or N/100 NaOH or KOH which is sufficiently free 
from carbonates to give a sharp end point with three drops of 
methyl red when used to titrate 5 mils of N/50 acid diluted 
with 20 mils of water. 
Sample 600 mg. 

Take a weighed amount of the powdered sample to yield not more 
than 140 mgms. of " crystallized " morphin. Brush into a 50-mil beaker. 
Fill a 50-mil measuring cylinder up to the 50 mark with water. Add 
30 mils of the water in the cylinder to the beaker. Stir with a glass rod, 



ALKALOIDS DERIVED FROM ISOQUINOLIN 215 

breaking up any lumpy particles, until the powder is dissolved as com- 
pletely as possible (there may be left a small amount of insoluble material). 
Transfer to a separatory funnel containing 14 to 14§ grams of finely pow- 
dered sodium chloride and 1 gram (weigh within 100 mgms.) of ammo- 
nium chloride. Use the remaining 20 mils of water in the cylinder, in 
several small portions, to rinse the beaker, draining completely both the 
cylinder and the beaker. Stopper the funnel and shake till the salt 
has dissolved. Add 10 mils of 95 per cent alcohol. From a burette or 
a pipette add 0.5 mil of concentrated ammonia. 

Immediately after the addition of the ammonia add 30 mils of chloro- 
form containing 5 per cent alcohol, stopper, and shake gently for one 
minute. When the layers have separated and there is no emulsion, draw 
off the chloroform, filtering through a small filter paper wetted with chloro- 
form, or through a small plug of cotton carefully wedged in the neck of a 
funnel and wetted with chloroform, into a beaker or flask. Repeat this 
process five more times with 15, 15, 10, 10, and 10 mils of chloroform 
respectively. In case of even slight emulsions the extraction of the alka- 
loid should be performed as follows. Draw off the chloroform layer 
together with the emulsified part into a second separatory funnel, and 
shake gently. In most cases the emulsion will dissappear or be greatly 
reduced. Draw off the chloroform, filtering into the beaker or flask. 
Treat the next shake-out in the same manner by drawing off both the 
chloroform and any emulsified part into the second separatory funnel, 
shaking and filtering. Repeat this process with each successive shake- 
out. In the case of emulsions not amenable to this treatment, the method 
as outlined cannot be used without suitable modifications. 

Evaporate or distill off the chloroform on the water-bath. Dissolve 
the residue by warming with about 10 mils of neutral alcohol, add 3 drops 
of methyl red, run in standard N/50 sulphuric acid until the indicator 
has turned red, then add a few mils in excess. Heat on the water-bath 
to insure the complete solution of the alkaloid. After cooling, titrate 
back with N/50 or N/100 alkali. 

One mil of N/50 acid corresponds to 6.00 mgms. of morphin IH2O 
(" crystallized "), and to 7.53 mgms. of morphin sulphate 5H 2 0. 

DETERMINATION OF SMALL QUANTITIES OF MORPHIN 

Small quantities of morphin present in opium in Chinese pills may 
be estimated very closely by converting it to heroin and weighing as such 
according to a procedure communicated to the author by Dr. H. A. Seil. 
The pills are exhausted with dilute acetic acid and if much gum is pres- 
ent the solution is poured into a considerable excess of alcohol and allowed 
to stand until the gum coagulates, after which it is filtered and the alcohol 
evaporated. The concentrated solution is transferred to a flask, 1-2 grams 



216 ALKALOIDAL DRUGS 

anhydrous sodium acetate added, boiled with an excess of acetic anhydride, 
cooled, and transferred to a separator with water and in 'the presence of 
cracked ice. The acid solution is shaken two or three times with chloro- 
form, separating the solvent and washing it with water, returning the 
latter to the acid mixture, and then the acid is neutralized with sodium 
bicarbonate, a slight excess being added. The heroin is then shaken 
out with ether and weighed after evaporating the solvent. 

COLORIMETRIC ESTIMATION OF MORPHIN AND CODEIN 

The estimation of small amounts of morphin or codein may be effected 
by the following colorimetric method of Carlinfanti, 1 a Wolff colorimeter 
being employed. The alkaloid is first isolated from the bulk of the sample 
by proper solvents, brought into solution with hydrochloric acid, and 
made up to a definite volume. In the case of morphin 1 to 5 mils are 
evaporated to dryness and cooled. The residue is dissolved in 5 mils of 
concentrated sulphuric acid, and the liquid introduced into a tube holding 
about 50 mils, fitted with a ground stopper; the dish is washed twice 
with 3 mils of concentrated acid, the washings added to the tube, which 
is then closed and immersed for fifteen minutes in a boiling water-bath. 
To the cooled tube is added 10 mils of a mixture of 100 mils of concen- 
trated sulphuric acid and two drops of nitric acid (sp. gr. 1.4); on shak- 
ing, the characteristic blood-red color appears. The solution is then intro- 
duced into the cylinder of the colorimeter. An aliquot of a 0.5 per cent 
solution of morphin hydrochloride (1 mil or more) is evaporated and the 
residue treated in the same way. The solutions in the tube are then 
matched by the addition of small quantities of concentrated sulphuric 
acid. 

In the case of codein the solutions of the sample and the standard 
are evaporated to about 1 mil by evaporation on a water-bath at 70-75°; 
15 to 20 mils of monohydrated sulphuric acid are added cautiously so 
that the mixture is not heated. The liquid is then introduced into a 
50-mil flask, the dish washed with 3 portions of monohydrated sulphuric 
acid, 5 mils each, and treated with 10 mils of a solution of monohydrated 
sulphuric acid 100 mils and 10 per cent ferric chloride 2 mils. After 
being shaken, the flasks are immersed for fifteen minutes in a water-bath 
at 80° C, the cooled solutions, which have assumed blue colorations, being 
introduced into cylinders of the colorimeter as before. 

ESTIMATION OF CODEIN IN OPIUM 

Dr. Caspari 2 has devised the following method for the estimation 
of codein in opium. Fifty grams of the sample are macerated with 500 
1 Boll. Chim. Farm., 1915, 54, 321. 2 Pharm. Review, 1904, 348. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 217 

mils of water for twelve hours with frequent agitation, filtered, and washed 
until the filtrate measures 750 mils, the residue is returned to the flask 
and shaken for fifteen minutes with 250 mils water, filtered and washed 
until this second filtrate measures 850 mils. The two filtrates are then 
combined, evaporated to 250 mils, treated with 5 grams barium acetate 
to precipitate the meconic acid and part of the resin, diluted to 700 mils, 
filtered, concentrated, and again precipitated with barium acetate. After 
filtering and washing the filtrate, a slight excess of 10 per cent sodium 
hydroxide is added which precipitates thebain, papaverin, and narcotin, 
leaving the codein, morphin, and narcein in solution; the mixture is fil- 
tered and washed after standing a short time. Concentrated hydro- 
chloric acid is then added to neutralize the alkali, followed by an excess 
of 2 per cent ammonia water, and the flask allowed to stand for several 
hours and then filtered from the precipitated morphin, which is washed 
and the filtrate concentrated and the treatment repeated to remove addi- 
tional morphin. The filtrate is rendered slightly acid with hydrochloric 
acid and concentrated to 75 mils, ammonia added in excess and the codein 
extracted with benzol. The solvent is then evaporated and the codein 
either weighed or titrated. 

A. E. Andrews * claims that the morphin carries down some of the 
codein in the above method and recommends the following procedure. 
Twelve grams of dry opium are exhausted with successive small quan- 
tities of water and the filtered solution adjusted to 100 mils; 20 mils of 
20 per cent lead-acetate solution added and after standing overnight, 
filtered rapidly on a Buchner filter; 100 mils of the filtrate, represent- 
ing 10 grams opium, are subjected to a stream of hydrogen sulphide to 
remove the lead, filtered, the lead sulphide washed and the washings 
concentrated before adding to the main filtrate, from which the hydrogen 
sulphide is expelled by a current of air. The solution which should amount 
to no more than 130 mils is well shaken with 20 mils of a 20 per cent solu- 
tion sodium salicylate and filtered from the resinous precipitate; a few 
crystals of thebain salicylate are added, the liquid stirred to facilitate the 
separation of any thebain as salicylate, and after standing overnight 
filtered through the same filter and the treatment repeated until no further 
separation occurs. The filter is then washed, the filtrate concentrated 
to 10-15 mils and while still warm, transferred to a separator, the rinsings 
being placed in a second separator. The solution is shaken three times 
with ether, the solvent each tune being used for extracting the rinsings, 
and the aqueous solutions are then united and treated with 10 mils of 
20 per cent sodium hydroxide and extracted four times with ether. The 
ether extracts are washed separately with two portions of water, united, 
dried with anhydrous sodium sulphate and distilled until only a few mils 

1 Analyst, 1911,489. 



218 . ALKALOIDAL DRUGS 

are left when the codein crystallizes out. The alkaloid is dried in vacuo 
weighed and titrated. 

CODEIN AND MORPHIN IN ADMIXTURE WITH CAFFEIN, ACETANILID, 
ACETPHENETIDIN AND QUININ 

Dr. W. 0. Emery 1 gives details of a method for the determination 
of codein, caffein, and acetphenetidin in pills and tablets of the cold and 
headache mixture type. 

Weigh out about 0.3500 gram of powdered material (if in pill or tablet 
form at least ten of these should be reduced to powder), transfer to a 
separatoiy funnel by means of 10 mils very dilute sulphuric acid (or suf- 
ficient to render the solution decidedly acid after neutralization of any 
carbonate that may be present), extract by means of vigorous shaking 
with 50 mils of chloroform. After clearing, draw off the solvent, allow- 
ing it to run through a small (5.5 cm.) filter into 200-mil Erlenmeyer. 
Distill off about 50 mils chloroform, using a small Bunsen flame. Extract 
a second and third time with the same amoimt of solvent as first used. 
Allow the chloroform from each extraction to run into the Erlenmeyer, 
then distill off all but about 10 mils. Now add 10 mils dilute sulphuric 
acid (1 volume concentrated acid to 5 of water) and heat on steam-bath 
until the chloroform has disappeared and only about 5 mils of the acid liquid 
remains, then treat as directed under caffein, page 837. Render the acid 
liquid in separator containing the codein sulphate neutral by the addition 
of solid sodium bicarbonate, wash out filter used in the preceding oper- 
ation to clarify the chloioform, once with water, allowing latter to run 
into the separator, then re-extract three separate times with 50 mils 
chloroform. Collect solvent as above directed in a second 200-mil Erlen- 
meyer, distilling off most of the liquid by the aid of gentle heat. Trans- 
fer residual chloroform to a small beaker or evaporating dish, using suf- 
ficient fresh chloroform for this purpose, heat gently over steam-bath 
to dryness, cool, and weigh as anhydrous codein. 

CAFFEIN, ACETANILID, QUININ SULPHATE AND MORPHIN SULPHATE IN 

MIXTURES. (W. O. EMERY.) 2 

Preparation of Sample and Solutions. — Transfer a separatory funnel 
an amount (containing not less than one-fourth grain of morphin) of the 
powdered sample equal to, or a multiple of, a unit dose, add 20 mils of 
water and 10 drops of dilute sulphuric acid, then extract with three 50-mil 
portions of alcohol-free chloroform, wash each portion in a second separa- 
tory funnel with 5 mils of water and add the combined washings to the 
alkaloidal solution in the first separatory funnel. Filter the chloroform 

1 U. S. Dept. Agri. Bu. Chem. Bull., 152, 239. 

2 J. Assn. Off. Agri. Chem., Vol. 1, page 360. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 219 

extracts through a small, dry filter into a 200-mil Erlenmeyer flask and 
distill by gentle heat to about 10 mils. • 

Caffein and Acetanilid. — The caffein and acetanilid will be present 
in the chloroform solution, while the quinin and morphin will be found 
in the acid liquid. If it is desired to separate and determine the caffein 
and acetanilid the analyst is referred to the methods described on pages 
837. 

Quinin Sulphate. — Add to the solution of quinin and morphin sul- 
phates, 4-5 mils sodium hydroxide solution (1 to 10) and extract with 
four 40-mil portions of chloroform, wash each portion with 5 mils of water 
and pass the clear solvent through a small, dry filter into a 200-mil Erlen- 
meyer flask. Remove the solvent by gentle distillation and titrate the 
residual quinin with N/50 hydrochloric acid as follows: 

Dissolve the amorphous alkaloid in 5 mils of neutral alcohol and titrate 
with N/50 hydrochloric acid to a faint red, using 2 drops of methyl red 
as an indicator. Heat on steam-bath until most of the alcohol has been 
expelled, adding, if necessary, sufficient acid to maintain the acid reac- 
tion. From the total number of mils of acid employed in the titration 
calculate the quinin sulphate. 

1 mil N/50 HC1 = 8.73 mg. quinin sulphate. 

Morphin Sulphate. — Wash the filter, employed above, with 5 mils of 
water and add to the aqueous alkaline solution of the alkaloid. Now 
add 0.5 gram of ammonium chloride (or an amount slightly in excess of that 
required to free the morphin as well as convert all sodium hydroxide to 
sodium chloride) and, to the resulting ammoniacal solution, add 45 mils of 
chloroform and 5 mils of alcohol, then extract in the usual way, washing the 
solvent in a second separatory funnel with 5 mils of water. After clear- 
ing, pass the chloroform through a small, dry filter into a 200-mil Erlen- 
meyer flask. Repeat the extraction with three 40-mil portions of chloro- 
form, washing and filtering as before, finally collecting all the solvent 
in an Erlenmeyer flask and distilling to about 10 mils. Transfer with 
chloroform to a small, tared beaker, evaporate to apparent dryness, add 
0.5 mil each of water and neutral alcohol, start crystallization by stirring 
with a glass rod and finally evaporate to dryness. Cool and allow to 
stand until the weight becomes constant. 

Check the weight of morphin, thus determined, by titration with N/50 
sulphuric acid, using a drop of methyl red as an indicator. Dissolve the 
alkaloid in 1-2 mils of warm, neutral alcohol, then add the standard 
acid to a faint red. Evaporate most of the alcohol on a steam-bath, 
adding, if necessary, sufficient acid to maintain the acid reaction. From 
the volume of acid used calculate the morphin sulphate. One mil of 
N/50 sulphuric acid is equivalent to 7.58 mg. of morphin sulphate. 



220 ALKALOIDAL DRUGS 

Note. — If the mixture contains acetphenetidin (phenacetin) in place 
of acetanilid, proceed as outlined above, except that the separation of 
caffein and acetphenetidin is conducted as directed on page 857. 

SEPARATION OF HEROIN AND MORPHIN. (J. M. DORAN) * 

The sample used should not contain over .2 gram of either heroin or 
morphin: if tablets dissolve in water slightly acidulated with hydro- 
chloric acid; if solid, treat with water acidified with dilute hydrochloric 
acid and filter; if an alcoholic solution, make slightly acid with dilute 
hydrochloric acid and evaporate off the alcohol before proceeding. 

Transfer the solution of the salts of the alkaloids to a separator, add 
a slight excess of ammonia, agitate with three separate additions of 25 
mils each of carbon tetrachloride, passing each fraction of solvent through 
a 7-cm. dry filter into a tared dish. Evaporate on a steam-bath to dry- 
ness, heat at 100° for ten minutes, cool, and weigh as heroin. The weight 
may be checked by titration. Doran recommends N/25 acid and the 
results may be calculated to the salt by the following factors: 

1 mil N/25 H2S04 = 0.01622 gram heroin hydrochloride or diacetyl 
morphin hydrochloride. 

1 mil N/25 H2SC>4 = 0.1694 gram of the monohydrated salt, which is 
the commercial article, and account should be taken of this condition 
in reporting on sample where the question of the amount present is of 
moment. 

For the determination of the morphin remaining as a free base in the 
ammoniacal solution the separations recommended above may be used 
to advantage. 

SEPARATION OF CODEIN, HEROIN, AND MORPHIN. (DORAN) 

If these three alkaloids occur in the same formula, the codein and 
heroin can be removed by carbon tetrachloride and weighed. The mor- 
phin can be determined in the ammoniacal solution as usual. 

Another portion of the solution of the sample may then be treated 
with 10 mils of N/2 NaOH, which completely hydrolyzes the heroin to 
morphin with the use of heat. The codein may then be extracted from 
the alkaline solution by carbon tetrachloride and weighed, the alkaline 
liquor containing the other alkaloids is acidified, then made alkaline with 
ammonia and the total morphin determined. 

GENERAL REMARKS ON THE ESTIMATION OF OPIUM ALKALOIDS 

The separation of morphin from complex mixtures cannot be accom- 
plished with the same ease as is the case, with quinin, strychnin, cocain, 
1 J. Ajner. Pharrn. Assn., 1916, 163. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 221 

and others which dissolve readily in immiscible solvents. We have 
observed the comparative facility with which these alkaloids can be 
removed from mixtures in the crude condition, and their final separation 
and purification brought about with certainty. From most mixtures 
morphin can be separated and its determination accomplished with cer- 
tainty, but the manipulations are not always simple. 

Opium and ipecac alkaloids are very often combined in medicinal 
products, but the complete separation of the two groups is still a matter 
of research. Emetin can be separated from cephaelin and of course mor- 
phin by shaking out with ether from a solution made alkaline with caustic 
alkali, but on subsequent extraction after rendering ammoniacal the 
cephaelin will come out with morphin. It is probable that the ipecac 
alkaloids will be practically all removed by making the solution alkaline 
with ammonia and shaking out with ether and subsequently removing 
the morphin with chloroform-alcohol. The mydriatic alkaloids, strychnin, 
aconitin, cocain, quinin, hydrastin, and sanguinarin can all be separated 
from morphin by shaking out with ether and chloroform from a solution 
made slightly alkaline with caustic alkali. 

When the sample consists of a pill or tablet of complex composition, 
the ground substance is extracted with alcohol, filtered, evaporated cau- 
tiously, the residue taken up with dilute acid and after adding alkali the 
alkaloids present are removed with ether or chloroform, and the morphin 
shaken out with chloroform and alcohol by either Eaton's or Buchbinder's 
procedure. Of- course if the product contains opium, the other alkaloids 
will be contaminated with the opium bases other than morphin, and if 
it is a question of determining the other alkaloids also the problem under 
these conditions will become more or less involved. 

Morphin pills can be dissolved in acidulated water, filtered from any 
insoluble material, and the morphin shaken out directly and purified. 
Tablets of morphin and atropin can be dissolved in acidulated water, 
the atropin shaken out with chloroform after rendering alkaline, and then 
after ammonia has been added the morphin can be removed by chloro- 
form and alcohol. 

Medicated lozenges should be dissolved in a small amount of water 
and the mixture, with any undissolved material, poured into an excess 
of alcohol about ten times the volume of the aqueous solution. After 
the gum has coagulated, the alcoholic solution is filtered off, the alcohol 
evaporated and the morphin separated from any accompanying alkaloids 
by the procedures mentioned above. 

Opium suppositories or opium ointments should be treated with petro- 
leum ether until the fats are all dissolved and the ether solution decanted 
through a filter, the residue washed with fresh petroleum ether and treated 
with acidulated water. The morphin can then be determined as in the 



222 ALKALOIDAL DRUGS 

opium assay. Qulnin sulphate has been found combined with opium in 
some pneumonia and croup remedies of the ointment class, and the quinin 
can be readily determined after the oils and fats are dissolved out with 
petroleum ether, by treating the residue with acidulated water, adding 
caustic alkali and shaking out with ether. On acidulating, adding 
ammonia and shaking out with chloroform-alcohol the morphin can be 
recovered. 

Morphin can be determined in liquids of the chlorodyne type by 
evaporating a measured quantity of the sample until the solvent and 
volatile ingredients have been driven off, dissolving the residue in acidu- 
lated water, removing the coloring matter and acid constituents by shak- 
ing the acid solution with ether and then separating the morphin as usual. 

Liquid preparations in general may be assayed for morphin according 
to Eaton's or Buchbinder's procedures with little preliminary manipu- 
lation, though if other drugs are of a resinous nature the solvent holding 
them in solution should be expelled and the residue then taken up with 
acidulated water and filtered from the resin. 

Codein can be removed from alkaline solution without any difficulty 
with ether or chloroform, and it seldom occurs with other alkaloids except, 
of course, when it is present in opium. It is sometimes combined with 
antipyrin, and no satisfactory separation has been as yet evolved. 

Heroin can be separated from its solutions by first shaking out the 
cold acid solution to remove neutral substances, and then freeing the 
heroin with sodium bicarbonate and extracting it with ether. The pre- 
cautions to be observed in working with this substance have already been 
noted. 

THE IPECAC ALKALOIDS 
Emetin, CsoIMOCHs^ (NH)N. 
CephaBlin, C25H 2 7(OCH 3 )3(OH)(NH)N. 
Psychotrin, C 2 5H26(OCH 3 )3(OH)N 2 . 

The roots of several species of. Ipecac contain the three alkaloids above 
mentioned. 

Hesse x reports in addition to the above, hydroipecamin, isomeric 
with cephselin, and ipecamin, isomeric with psychotrin. He attributes 
slightly different formulas than those above which were determined by 
Carr and Pyman 2 and confirmed by Karrer. 3 

The United States Pharmacopoeia recognizes two ipecacs, at least they 
are regarded by some authorities as distinct species, while in other quar- 

1 Annalen, 1914, 405. 2 Chem. Soc. Trans., 1914, 105, 1591. 

3 Ber., 1916, 49, 2057. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 223 

ters they are considered to be simply variations of the same species. They 
are designated Cephselis ipecacuanha, known commercially as Rio, 
Brazilian, or Para ipecac, and C. acuminata, known as Carthagena ipecac. 

Rio ipecac is dark brown in color and closely annulated with thick- 
ened incomplete rings exhibiting transverse fissures with vertical sides; 
the bark is thick and light brown, easily separable from the yellowish 
white wood. Carthagena ipecac is usually thicker than Rio and is of a 
grayish-brown color, with fewer annulations which are occasionally trans- 
versely fissured with circular scars of bark; the bark is dark brown, 
smooth, and horny, the wood light brown. Both varieties have dark brown 
stems, wrinkled longitudinally. 

It is generally reported that C. acuminata contains more cephaelin 
in proportion to the emetin than is the case in C. ipecacuanha. Indian- 
grown root resembles Brazilian root more closely than Carthagena. 

The official roots contain from 1.75 per cent to about 3 per cent of 
total alkaloids. There is also present a plant acid called ipecacuanhic 
acid, which is claimed to be a glucoside of the saponin class, and which is 
supposed to be the active constituent of the product known commercially 
as de-emeiinized ipecac. This product is really a " de-alkaloid ed " 
ipecac, but it often contains considerable quantities of alkaloids. Finne- 
more and Braithwaite x have studied a substance which they claim is 
identical with ipecacuanhic acid and which they call ipecacuanhin. It 
appears to be a glucoside containing a catechol complex and yields on 
hydrolysis with emulsin a sugar producing an osazone, melting 207°. 
It is soluble in ether, petroleum ether, and hot water, but only sparingly 
soluble in chloroform. When given intravenously it had no physiological 
action on rabbits. Various plants have been offered for sale for ipecac, 
some being species of Cephaelis, and others belonging to other genera. 
There are also a number of wild or false ipecacs, some of which have 
obtained more or less recognition in medicine: 

Undulated ipecac from Richardsonia scabia. 

Striated ipecac from Cephselis emetica. 

American ipecac, Porteranthus gillenia stipulatus. 

Indian Physic, P. trifoliatus; roots resemble P. gillenia but are not 

annulate. 
Goanese ipecac, Naregamia alata. 
East Indian Root, Cryptocorye spiralis. 
White ipecac, Hybanthus ipecacuanha (Violacese). 
White ipecac (Poaya blanca) Polygala angulata. 
Anchieta salutaris. 
Viola odorata. 

1 Pharm. J., 89, 136, 176. 



224 ALKALOIDAL DRUGS 

Triosteum perfoliatum. 

Heteropteris pauciflora. 

The roots of several of the Euphorbiacese are used as emetics. 

Ipecac spurge — Euphorbia ipecacuanha. 

Purging or Emetic root — E. corallata syn. Tythymalopsis corallata. 

Examination of samples of recent (1916-17) importations of ipecac 
has disclosed that Heteropteris pauciflora, Ipecacuanha fibrosa, and an 
Ionidium species have been substituted for true Cephselis. 

Ipecac is noted for its emetic and expectorant properties, it is used in 
small quantities as a tonic and often occurs in remedies recommended for 
dysentery, dyspepsia, and pyorrhoea. Ipecac will be found in a number 
of combinations used in medicine, and the mixed alkaloids, under the 
name of " emetin," will be encountered occasionally as the sole active com- 
ponent of a pill or tablet. One of the best known products containing 
ipecac is Dover Powder, which consists of equal parts of powdered ipecac 
and powdered opium with sugar of milk. This mixture is sold as a powder, 
alone and in pills and tablets, and mercury mass; mercury with chalk, 
calomel, or quinin sulphate will sometimes be found as additional ingredi- 
ents; combinations of ipecac and calomel; and ipecac and squill with 
ammonium salts are of common occurrence. Aloin, belladonna, strychnin, 
and ipecac is a mixture widely used, and some special laxatives include this 
combination with the addition of rhubarb, colocynth, and Podophyllum. 
Other mixtures include ipecac with strychnin, pepper, gentian, cloves, 
Capsicum, and sodium bicarbonate; with colocynth and mercury mass; 
with Conium; with morphin, potassium nitrate, and camphor; with mer- 
cury mass and Gelsemium; with Podophyllum and camphor; with acet- 
phenetidin, quinin, aconite, and opium; with phosphoius, opium, and 
Digitalis sometimes with the addition of quinin; with strychnin, arsenous 
acid, reduced iron, quinin, or cinchonidin; with bismuth subnitrate 
and calomel; with nickel bromide, codein, Kthium carbonate, and anise 
in anodynes for infants; with ammonium chloride, opium, licorice, and 
belladonna in cough mixtures; with opium, lead acetate, and camphor; 
with aconite, morphin, and tartar-emetic in fever compounds; with pepsin, 
Capsicum and Nux Vomica, gentian and sodium bicarbonate in anti- 
dyspeptic mixtures; with senega, tolu, cubeb, ammonium chloride, lic- 
orice, and Hyoscyamus in bronchial tablets; with Sanguinaria, morphin, 
atropin, aconite, tar, and tartar-emetic in cough mixtures; and with white- 
pine bark, wild cherry, squill, senega, Sanguinaria, opium, and potas- 
sium nitrate for the same purpose; with cerium oxalate for nausea. Loz- 
enges of ipecac, and ipecac with morphin and antimony are well known. 

Ipecac is combined with senega in a mixed fluid extract of the two 
drugs; with cimicifuga, senega, wild cherry, and licorice in a liquid com- 



ai 



ALKALOIDS DERIVED FROM ISOQUINOLIN 225 

pound; and ipecac is dispensed in the form of wine and syrup both with 
and without opium. Syrup of morphin compound contains ipecac, senega, 
rhubarb, morphin, and oil of sassafras; and syrup of Irish moss (syrupus 
chondri compositus) contains Irish moss, ipecac, squill, senega, and opium. 



Emetin 

Emetin is an amorphous alkaloid, nearly colorless when pure, but 
becoming darker on exposure to light. It is strongly alkaline and com- 
pletely neutralizes acids. It melts about 70° C, is optically inactive. 
is slightly soluble in water and petroleum ether, and dissolves readily in 
alcohol, ether, chloroform, and benzol. 

It forms well-defined salts. The sulphate, acetate, and oxalate are 
amorphous and readily soluble in water. The hydrochloride is crystal- 
line and also dissolves in water. The hydrobromide and hydriodide are 
sparingly soluble and separate on adding a soluble bromide or iodide to 
a solution of emetin hydrochloride. The nitrate is also sparingly solu- 
ble and may be obtained as a resinous mass on adding potassium nitrate 
to a solution of the hydrochloride. 

When warmed on the water-bath with benzoic anhydride, emetin 
yields \benzoyl emetin, which crystallizes from absolute alcohol in white 
needlesTrneKmg iSS^TSG C. The cooled melt should be dissolved in 
ether, the derivatives shaken out with dilute sulphuric acid, the acid 
solution treated with ammonia and shaken with ether. On evaporation, 
the benzoyl-emetin will be left and can be crystallized out of absolute 
alcohol. 

Emetin hydrochloride boiled with ferric chloride, gives rubremetin 
hydrochloride, a scarlet substance, soluble in chloroform, melting, when 
air-dried, at 127-128° with decomposition, 

Cephaelin 

This alkaloid, when freshly precipitated, is colorless but soon turns 
yellow. It is optically inactive. It melts at various temperatures, depend- 
ing on the manner in which it is deposited. An alcoholic or ethereal solu- 
tion on evaporation leaves the base as a transparent varnish. It may 
be obtained crystalline from an ethereal solution in a closed vessel. It 
is much more soluble in petroleum ether than emetin, and differs from 
that alkaloid by dissolving readily in alkali hydroxides. 

Cephaelin on methylation with sodium methyl sulphate and sodium 
amyloxide yields emetin, the OH group being methylated. With methyl 
sulphate and sodium methoxide the imino group is methylated principally, 
forming N-methyl cephaelin, melting 194-195° C. 



226 ALKALOIDAL DRUGS 



Psychotrin 

Psycho trin occurs in small amount in ipecac. It crystallizes in yel- 
low prisms, melting 138°, readily soluble in alcohol, chloroform, and alka- 
lies, but only sparingly soluble in ether, thus differing from emetin and 
cephselin. Its solution in ammonia shows a blue fluorescence. 

These alkaloids are always so intimately associated with each other 
that their analytical reactions will be discussed under one heading and 
not under the separate alkaloids. 

The mixed alkaloids give an orange or lemon-yellow color when treated 
with a solution of calcium hypochlorite, followed by a drop of acetic acid. 

They are precipitated from acid solution by the usual alkaloidal pre- 
cipitants and yield various colors with sulphuric acid and oxidizing agents, 
but none of them are especially characteristic. Sulphuric acid produces 
a pale yellow becoming brown on warming. 

Allen and Scott-Smith 1 have given details of a careful study of the 
color tests with special reference to the similarity of certain reactions 
with those given by the opium bases. 

The authors have established that the alkaloids give with ferric chlo- 
ride a blue color, later changing to green, while the opium alkaloids, pro- 
duce a blue-green color from the very beginning. 

Froehde's reagent gives with the ipecac alkaloids a purple-bluish- 
violet color, resembling the known reactions of the opium alkaloids but 
not such a pure color as afforded by morphin. 

Iodic acid and starch frequently, but not always, give with the ipecac 
alkaloids the same blue color as with the opium alkaloids. Likewise both 
groups of alkaloids reduce in a similar manner the mixture of ferric chlo- 
ride and potassium ferricyanide with the production of a blue color. The 
individual ipecac alkaloids exhibit different modifications and the reactions 
in part are not so sharp. Psychotrin appears to be the chief cause of the 
chief reaction with ferric chloride and iodic acid, but the possibility is 
not excluded that this reaction is produced by a new ipecac alkaloid, for 
if one treats the ipecac extract with lead acetate and decomposes the lead 
precipitate in the usual manner, a substance may be obtained with 
amyl alcohol from acid solutions, which at once reduces iodic acid, and mix- 
ture of ferric chloride and potassium ferricyanide. If the acid solution 
which has been extracted with amyl alcohol is made alkaline with sodium 
bicarbonate and again treated with amyl alcohol a residue is obtained 
which turns blue-green with ferric chloride, dirty purple red with Froehde's 
reagent, and blue with iron chloride and potassium ferricyanide. The 
ipecac alkaloids may to a certainty be distinguished from those of opium 
by the use of Froehde's reagent and hydrochloric acid. 

1 Pharm. Post, 1903, 348. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 227 

Emetin gives with Froehde's reagent a dirty-green color which turns 
grass-green on the addition of hydrochloric acid. Cephselin turns purple- 
red upon addition of hydrochloric acid and immediately changes to Prus- 
sian blue. Psychotrin gives with Froehde's reagent a dull-purple color 
which is turned dull-green by hydrochloric acid. The ipecac alkaloids 
collectively (total alkaloids) turn purple-bluish to violet with Froehde's 
reagent and after addition of hydrochloric acid (analogous to psychotrin) 
give an intense blue. Opium alkaloids with Froehde's reagent give a 
characteristic purple color which, however, is caused to disappear by 
hydrochloric acid. 

Lowin 1 states that emetin and cephselin can be distinguished by the 
following tests: with Millon's reagent a 1-50 solution of emetin remains 
colorless in the cold, but turns yellowish on heating; a solution of cephselin 
turns violet in the cold and on heating becomes finally dark brown, while 
color changes are obtained very distinctly with a 1-1000 and are just 
visible with a 1-5000 solution. With mercuric acetate a 1-50 solution of 
emetin remains unchanged in the cold, and becomes somewhat yellowish 
and turbid on heating; a cephselin solution is colorless in the cold, but 
becomes violet and later dark grayish brown on heating, a 1-5000 solu- 
tion of the alkaloid giving a distinctly visible reaction. 

The microscopic examination of crystallized psychotrin furnishes valu- 
able evidence in the detection of ipecac alkaloids. A chloroformic solution 
of the alkaloid is shaken with a little dilute acid, and the acid solution 
concentrated and transferred to a watch-glass or microscopic slide fur- 
nished with a cell. A watch-glass or beaker is then moistened on the inside 
with ammonia and inverted over the acid solution. The ammoniacal 
vapors are absorbed by the liquid and the alkaloid is liberated, separating 
in characteristic crystals. Psychotrin forms very minute crystals which 
appear to belong to the regular system, many of them appear to be octa- 
hedra and are very similar to microscopic crystals of arsenous oxide, 
while others closely resemble granules of rice starch. 

In order to separate emetin and cephselin, a solution of the alkaloids 
in hydrochloric acid is treated with a slight excess of dilute potassium 
hydroxide and shaken with ether. The ether solution, after separating, 
is shaken with dilute alkali, and the latter, after washing with ether, is 
added to the original aqeous solution, which should now contain all of the 
cephselin, the emetin being in the ether, and may be obtained on evapo- 
ration. To recover the cephselin, the alkaline solution is treated with a 
slight excess of hydrochloric acid, then made ammoniacal and the alka- 
loid removed by a mixture of ether-chloroform (1-6). 

A conclusive identification of these alkaloids when they are present 
in small quantities is not very satisfactory. It can often be stated with 
1 Chem. Zeit., 1903, 27, Rep. 25. 



228 ALKAL01DAL DRUGS 

assurance that the residue under examination does not contain alkaloids 
giving sharply defined tests, though the reactions obtained may indicate 
erne tin and cephselin. Again it is not always easy to detect these bases 
when other alkaloids are present. If ipecac alkaloids are suspected it 
is a good rule to use as much of the sample as can be spared so that a suf- 
ficient quantity can be obtained for preparing the identification tests. 

The similarity between certain of the tests of these alkaloids and those 
of opium has already been noted, but any doubt as to the presence of the 
latter may be set at rest by treating a portion of the residue with form- 
aldehyde-sulphuric acid, which gives the characteristic purple with opium 
bases. 

The tests given by the Nux Vomica and belladonna alkaloids are not 
obscured by the presence of the ipecac bases. 

In case it becomes necessary to determine the presence of ipecac bases 
in a complex mixture of alkaloids, the best plan is to separate the cephselin 
by taking advantage of its solubility in alkali hydroxides by a procedure 
similar to that described above for separating emetin and cephselin. After 
recovering the latter and establishing its identity, the presence of ipecac 
in the sample may be asserted. 

ALKALOIDS FROM HYDRASTIS CANADENSIS, BERBERIS AQUIFOLIUM AND 
OTHER SPECIES OF BERBERIS, AND ALLIED ALKALOIDS 

Hydrastin, C2iH 2 iN0 6 . 
Hydrastinin, C11H13NO3. 
Berberin, C20H17NO4. 
Canadin, C20H21NO4 

(Z-tetrahy droberberin) . 
Nandinin, C19H19NO4. 
Oxyacanthin, C19H21NO3 or C18H19NO3. 
Berbamin, C18H19NO3. 
Jeteorrhizin, C20H19NO5. 
Columbamin, C21H21NO5. 
Palmatin, C 2 iH 2 iN0 6 . 

The most important alkaloid of this group is hydrastin, which occurs 
in the rhizome of Hydrastis canadensis (Ranunculacese), Golden Seal, 
in amounts varying from .5 to 3 per cent, and is accompanied by canadin 
and berberin. Berberin is widely distributed, being found in Hydrastis, 
the roots of Berberis aquifolium (Berberidacese) or Oregon grape, B. vul- 
garis, common barberry, B. nervosa, B. pinnata and others, Coptis tri- 
folia (Ranunculacese), gold thread, C. teeta, and probably many other 
botanical species. Oxyacanthin accompanies berberin in the Berberis 



m 



ALKALOIDS DERIVED FROM ISOQUINOLIN 229 

genus, and berbamin is found in B. vulgaris. The last three alkaloids 
mentioned have been isolated from the root of Jeteorrhiza Calumba, 
Calumba root which was formerly supposed to contain berberin, and they 
were probably mistaken for this alkaloid. 

Hydrastis, owing to its high intrinsic value, is liable to adulteration, 
and samples of the ground drug should always be examined very care- 
fully under the microscope. It will be found mixed with some of the native 
root drugs, serpentaria, Cypripedium, senega, Collinsonia, Jeffersonia, 
Trillium, etc., and according to Lloyd the whole drug has been found 
wholly or in part substituted by Stylophorum diphyllum. 

Preparations containing Hydrastis, or the alkaloids lrydrastin and ber- 
berin, are used for a number of different purposes. Golden Seal has tonic 
properties, and is claimed to increase the intestinal secretions and pro- 
mote the flow of bile. It is used in gastric catarrh, dyspepsia, and for 
troubles affecting the mucous membranes of the mouth, throat, nose, and 
genito-urinary organs, and the alkaloids should be sought in medicines 
exploited for these purposes. Berberis is used as a tonic and blood puri- 
fier, in syphilis, scrofulous complaints, psoriasis, etc., and Coptis trifolia 
has long been known as a remedy for canker and various forms of ulcer- 
ated and sore mouth. The latter is often administered as a masticatory, 
and is combined with other drugs in gargles and bitter tonics. 

Of the combinations met with in practice may be mentioned pills 
and tablets containing the extract of Hydrastis with morphin and certain 
astringent substances as alum, zinc sulphate, tannic acid, guaiac, boric 
acid, etc., sold for astringent washes and uterine antiseptics; berberin 
and podophillin, and extract of Berberis aquifolium and Cascara sagrada; 
elixirs containing Berberis with Cascara and licorice; berberin and iron 
pyrophosphates; Hydrastis, rhubarb, and potassium bicarbonate; tonics 
containing Hydrastis, senna, iron, and aromatics; utero-ovarian seda- 
tives and anodynes containing Hydrastis, Viburnum prunifolium, and 
Piscidia piscipula (Jamaica Dogwood), this same mixture being sold also 
in tablet form. 

Hydrastin is sold in the form of tablet triturates, and the hydrochlo- 
rate has considerable use in eye remedies. Hydrastinin hydrochlorate, 
prepared synthetically from hydrastin, is used in menorrhagia and for 
arresting postpartum hemorrhage. 

The term " Hydrastin " is also applied to a concentrated resinous 
extract obtained from the root. 

Calumba root is a mild, non-astringent tonic, and as it contains no 
tannin may be combined with iron, hence it majr be suspected in iron tonics. 
In tablet form it is offered combined with Nux Vomica, Cinchona, gentian, 
phosphorus, and chamomile. In liquid form it is used with ginger, senna, 
and other tonics, aromatics, and mild cathartics. 



230 ALKALOIDAL DRUGS 

Hydrastin 

OCH3 

I 

c 

•\ 

HC COCH3 

) II 
HC CCO 

V 

c 

I 

HC O 

I 
HC CH 



/ 



O— C C NCH 3 

I II I 
0— C C CH 2 



C C 
H H 2 

Hydrastin, the white alkaloid of the Golden seal root, occurs in nature 
partly in the free state and partly combined. It crystallizes from alcohol 
in prisms, melting at 132° C, insoluble in petroleum ether, very slightly 
soluble in water, but dissolving in chloroform, benzol, ether, and alcohol, 
chloroform being by far the best solvent. It is a weak base, insoluble 
in alkalies, and may be completely removed by chloroform from solutions 
acidified with hydrochloric acid, resembling narcotin in this respect, to 
which it is closely related constitutionally. Its solutions in solvents are 
strongly dextrorotatory, and its acid solution is lsevorotatory. It is pre- 
cipitated by most of the ordinary alkaloidal precipitants, potassium bichro- 
mate and picric acid, but does not give precipitates with bromine water 
nor potassium iodide as is the case with berberin. The picrate, recrys- 
tallized from boiling alcohol, forms lustrous yellow needles, melting 165- 
170° C. 

The precipitate formed with bichromate becomes bright red or pink- 
ish violet when touched with concentrated sulphuric acid, differing in 
this respect from the colors given by strychnin or gelsemin under similar 
conditions. 

Hydrastin yields protocatechuic and formic acids when fused with 
potassium hydroxide. On treatment with oxidizing agents opianic acid 
and hydrastinin are formed, according to the equation: 

C21H21NO6+H2O = CioHioOo+CuHisNOs 

Sulphuric acid when pure gives no color with hydrastin, but in the 
presence of potassium bichromate a brown color, changing to pinkish 



ALKALOIDS DERIVED FROM ISOQUINOLIN 231 

violet, is produced; neither manganese dioxide nor hydrogen dioxide give 
any color. A solution of hydrastin in dilute sulphuric acid gives a yellow 
precipitate with bichromate, the precipitate when freed from liquid and 
touched with sulphuric acid gives a pink-violet color, soon fading. 

Ammonium vanadate reagent produces a pink coloration, soon chang- 
ing to bright red and then gradually to~ brick red, entirely different from 
that produced with strychnin. Froehde's reagent, freshly prepared, gives 
no reaction when first added, but on standing a deep-green color gradually 
develops. Sulphuric acid containing formaldehyde causes no color, in 
marked contrast to narcotin, whrch gives a purple. With nitric acid a yel- 
low shade is produced, but there is nothing characteristic about it. 

A solution of hydrastin in dilute sulphuric acid develops an intense 
blue fluorescence when a drop or two of N/10 permanganate is added. 
The fluorescent substance is not removed by ether or chloroform, differ- 
ing thereby from esculin. 

Labat 1 makes use of the formation of opianic acid for detecting hydras- 
tin. The alkaloid is oxidized in acid solution with permanganate and 
then alcohol added, the concentration being adjusted in order to obtain 
a 1 per cent solution of opianic acid. 2-mil portions of concentrated sul- 
phuric acid are treated with 0.1 mil of the alcoholic solution and then 
tested with certain phenols; 0.1 mil gallic acid produces a blue color, 
fading to brown on warming; guaiacol, red changing to blue; a-naph- 
thol, a gooseberiy red; /3-naphthol, a wine red; codein, violet to blue; 
/3-methylnaphthol, violet soon fading. The same reactions are observed 
with narcotin and hydrastin. 

Hydrastin forms condensation products with acetone and certain other 
ketones. 

The salts of hydrastin which occur on the market are the hydrochlo- 
ride and sulphate. The hydrochloride is readily formed when a solution 
of the alkaloid in absolute ether is brought in contact with In^drogen 
chloride gas. Both salts dissolve readily in water. The hydrobromide 
and hydriodide also occur, but have little or no use in medicine. The 
hydriodide is the least soluble of the four. 

Hydrastinin 
H / H 

c c=o 



H 2 a 



O— C C NHCHs 

I II I 
O— C C CH 2 



c c 

H H 2 
i Bull. Soc Chim., 1909, 5, 743. 



232 ALKALOIDAL DRUGS 

Hydrastinin in the form of its hydrochloride has a limited use in medi- 
cine and is an artificial alkaloid, produced, together with opianic acid, 
on oxidizing hydrastin. The crystalline hydrochloride is formed by pass- 
ing dry hydrogen chloride through a chloroform solution of the base. 

Hydrastinin crystallizes in needles, melting 116-117°, slightly soluble 
in water and dissolving readily in the ordinary organic solvents, includ- 
ing petroleum ether. It is inactive. Its solution in water is alkaline and 
exhibits fluorescence and its alcoholic solution is fluorescent. It com- 
bines with hydroxylamine and forms benzoyl and acetyl derivatives. 

A solution of the hydrochloride when treated with a few drops of 
Nessler's reagent gives a precipitate which blackens instantly. Morphin, 
apomorphin, and picrotoxin also reduce Nessler's reagent and are, accord- 
ing to Jorissen, the only other principles which give a reaction similar to 
hydrastinin. It also reduces Tollen's reagent. 

The color reactions given by hydrastinin with concentrated sulphuric 
acid, ammonium vanadate, and Froehde's reagent are the same as those 
given by hydrastin. Its solution in dilute sulphuric acid, when treated 
with a drop or two of permanganate, shows fluorescence on dilution. 

Hydrastin on benzoylation with benzoic anhydride or benzoyl chloride 
yields a benzoylated compound melting 98-99° when crystallized from 
dilute alcohol. When warmed with acetic anhydride in benzole solution 
it yields an acetyl derivative, melting 105°. 

Berberin 

H H 2 

C C 

/O— C C CH 2 

H 2 C< | || | 

x O— C C NOH 

C C CH 

H || | 
CH C 

\^\ 
C C-OCHs 

I I! 

CH C-OCHs 

V 

c 

H 

When pure, berberin is a yellow alkaloid, the melting-point of which 
has not been definitely determined. It usually contains varying amounts 
of water which, according to some authorities, is entirely driven off at 
100° C. Most of its salts are less soluble in water than the free alkaloid, 



ALKALOIDS DERIVED FROM ISOQUINOLIN 233 

thus the hydrochloride requires 500 parts of water to keep it in solution, 
and is nearly insoluble in dilute hydrochloric acid. 

It has a bitter taste, is a weak base somewhat soluble in cold water, 
alcohol, and amyl alcohol, and readily soluble on warming, slightly soluble 
in chloroform and benzole, and insoluble in ether and petroleum ether. 
Chloroform and benzole will remove it from both acid and alkaline solu- 
tions to a limited extent, but it is best removed from solutions by a mix- 
ture of alcohol and choloroform. It is readily separated from oxyacan- 
thin and hydrastin through its insolubility in ether. 

Berberin forms crystalline derivatives with acetone and chloroform, 
from which the free base may be liberated by wanning in alcoholic solu- 
tion. 

Berberin is precipitated by nearly all of the ordinary alkaloidal pre- 
cipitants, Mayer's and Wagner's reagents, potassium iodide and chromate, 
picric acid, platinic chloride, gold chloride, bromin water, and hydro- 
chloric and sulphuric acids if not too dilute. Concentrated sulphuric 
acid dissolves berberin to an orange-yellow solution, which becomes olive 
green on warming, and on adding bichromate a violet shade changing 
to brownish green takes place. Under some conditions, depending on 
the purity of the residue, a black color will be observed on adding the 
oxidizing agent, soon changing to chocolate brown and then violet. 

Froehde's reagent produces a greenish brown to dark brown or violet. 
Nitric acid dissolves berberin to a dark reddish-brown liquid, which on 
dilution with water gives a yellow precipitate partially soluble in ammonia. 
When a solution of berberin strongly acidified with hydrochloric or sul- 
phuric acids is treated with a small quantity of chlorine water, cautiously 
added from a pipette and allowed to rest on the surface of the liquid to 
be tested, a zone of bright red is formed at the junction of the two liquids. 
A fragment of sodium nitrate stirred into a solution of berberin in con- 
centrated sulphuric acid gives a violet streak, 

Canadin, Z-tetrahydroberberin 

This alkaloid, in the laevo form, is present in small amount in Hydras- 
tis root; it melts 132.5-137° and is soluble in the ordinary organic sol- 
vents with the exception of petroleum ether, which dissolves it sparingly. 
It is insoluble in water. An alcoholic solution of iodine converts it into 
berberin. 

Tetrahydroberberin occurs in three forms, the dextro modification 
melting at 139-140°. The racemic form splits into its constituents by 
precipitating with ortho-bromcamphorsulphuric acid. Hlascwitz and Gilm 
obtained tetrahydroberberin, melting 167°, by reducing berberin with zinc 
and sulphuric acid. 



234 ALKALOIDAL DRUGS 

Canadin liberates iodine from iodic acid and gives Prussian blue with 
potassium ferricyanide and ferric chloride. Its color reactions are not 
especially characteristic; sulphuric acid dissolves it to a yellow solution, 
gradually turning red, and nitric acid gives a yellow solution. Ammo- 
nium vanadate gives an olive-green color turning to dark black-brown. 

Oxyacanthin 

Oxyacanthin accompanies berberin in several species of Berberis and 
is readily separated from berberin by its solubility in ether. When thrown 
out of an acid solution with ammonia it is obtained in an amorphous form 
melting 138-150°. It may be crystallized out of alcohol or ether in the 
form of needles melting at about 210°. It is dextrorotatory and soluble 
in organic solvents, sparingly in petroleum ether, and partly removed from 
its acid solution by chloroform. The form in which it ordinarily occurs 
is known as the alpha modification, and as such, is soluble in sodium 
hydroxide with great difficulty; on treatment with potassium or barium 
hydroxide it is converted into the beta form which is readily soluble in 
potassium hydroxide, and cannot be removed from such a solution with 
ether. Ammonium chloride precipitates the beta modification from its 
solution in potassium hydroxide and this precipitate on drying goes over 
to the alpha form. 

Oxyacanthin liberates iodine from iodic acid, from potassium iodide 
in dilute sulphuric acid, and gives Prussian blue with ferric chloride and 
potassium ferricyanide. With Froehde's reagent it gives a violet color 
turning blue or green and gradually fading to yellow. Ammonium van- 
adate gives a dirty violet. 

Berbamin 

This alkaloid occurs with oxyacanthin and berberin in Berberis and 
may be separated from the former by petroleum ether in which it is insol- 
uble. The free base melts 197-210° according to Rudel. Its color and 
reducing reactions are similar to those of oxyacanthin. 

Nandinin 

Eykman reported this base as occurring in the root of Nandina domes- 
tica, but its properties and composition have apparently never been pub- 
lished. 

When these alkaloids of Calumba are extracted from liquid mixtures 
the residue is easily mistaken for berberin, the color reactions are some- 
what similar and the precipitates obtained and general character of the 
mixture suggest this alkaloid. For this reason the absence of calumba 
bitter, " calumbin " should be established unless one is certain that he 



■■ 



ALKALOIDS DERIVED FROM ISOQUINOLIN 235 

is dealing with a berberin-bearing drug instead of calumba. The three 
alkaloids from calumba all form yellow salts. 

Columbin 

This substance is a neutral princip^ and is intense^ bitter. Inves- 
tigation has demonstrated that it is a chemical individual, probably of 
lactone constitution, possessing two hydroxyl groups and melting at 
182° C. Its formula is given as C28H 3 o09 : 3 It gives a diacetyl deriva- 
tive, melting at 218° and crystallizing iff white needles. Pure columbin 
is slightly soluble in cold water, alcohol, and ether, but goes into solution 
more readily on warming. It may be removed from an acid aqueous 
solution by shaking out with ether, and the residue left on evaporation 
purified by crystallizing the columbin out of alcohol or ether, decolor- 
izing if necessary by shaking witrTdry animal charcoal and filtering. 

Columbin gives an orange color changing to red on treatment with 
concentrated sulphuric acid, the solution throwing out brown flocks on 
dilution with water. Boiling alkalies and lime water convert columbin 
to columbic acid, melting 228°, slightly soluble in ether and water and 
readily soluble in alcohol. 

Columbin is not precipitated by the usual organic precipitants, and 
may be removed from an acid solution by ether after precipitating the 
alkaloids by Mayer's reagent. 

In this group the analyst will be concerned chiefly with the separation 
and identification of berberin, hydrastin, and hydrastinin ; and occasion- 
ally to identify columbin, and to differentiate between the columba alka- 
loids and those from Berberis. The other alkaloids mentioned are not 
used commercially. Berberin or hydrastin, when alone, are easy of identi- 
fication. Mixtures containing Hydrastis nearly always give indications of 
the presence of this drug through the fluorescence imparted to the ether 
shake-outs. 

In order to remove the alkaloids from the rest of the drug, and the 
other ingredients in the medicine, the sample or an evaporated residue 
of a liquid portion should be triturated four or five times with successive 
portions of 95 per cent alcohol in an evaporating dish, the united alcoholic 
extractions evaporated over the steam-bath, and the residue dissolved 
in dilute acid and subjected to the regular scheme of alkaloidal separation. 

Hydrastin may be completely separated from berberin by shaking 
out with absolute ether from a slightly alkaline solution, and berberin 
may be subsequently removed by alcohol-chloroform mixture. As obtained 
in this way, hydrastin will be contaminated with canadin, which may be 
separated from hydrastin by dissolving the residue in dilute acid, render- 
ing alkaline and shaking out with petroleum ether, in which hydrastin 
is almost insoluble. If the drug product under investigation contains 



236 ALKALOIDAL DRUGS 

Berberis, the ether will remove oxyacanthin and berbamin. Berberin may 
also be removed from a residue of mixed alkaloids by dissolving in alcohol, 
diluting with water and precipitating with 10 per cent potassium iodide. 

It will often happen that some of the oxymethylanthroquinone drugs 
will be present in mixtures with Hydrastis or Berberis, and the resi- 
dues obtained therefrom will be contaminated with substances which will 
alter the color tests. These bodies may be eliminated by shaking the 
ethereal solutions of the alkaloids with dilute ammonia; or the alkaloids 
may be precipitated from an acid solution by Mayer's reagent, the pre- 
cipitate filtered, washed, dissolved in alcohol, and the alkaloids again 
liberated by alkali and removed by suitable solvents after diluting the 
solution with water. 

Quantitative Estimations. — For the estimation of hydrastin in pills 
or tablets containing Hydrastis extract, the sample should be ground and 
triturated in a mortar with 95 per cent alcohol, the alcoholic extract 
filtered into an evaporating dish, the procedure repeated three times, and 
the filter finally washed with a fresh portion of alcohol. About 10 mils 
of water are then added to the contents of the dish and the alcohol evapo- 
rated over the steam-bath. The residue is then treated with water and 
dilute sulphuric acid, filtered into a separator; ammonia added in slight 
excess and the hydrastin removed by shaking out four times with absolute 
ether. The ethereal extract is shaken out with dilute hydrochloric acid, 
the acid solution rendered alkaline with ammonia, and the hydrastin 
removed by shaking out four times with ether. The ether extract is then 
washed once with water, filtered into a tared dish, the solvent evaporated 
and the residue weighed as hydrastin. 

If the sample is a liquid it should be evaporated over the steam-bath 
until the alcohol and water are expelled, the residue treated with alcohol 
and the determination finished as above. 

Berberin may be determined, when it occurs in mixtures with hydras- 
tin, by precipitating the acid solution with potassium iodide which removes 
the berberin. The hydrastin may then be determined in the filtrate and 
the berberin converted into the acetone compound and the estimation 
completed according to Gordin's 1 method. The procedure is as follows: 
the precipitated hydriodide is washed with a 2 per cent solution of potas- 
sium iodide and then washed into a flask; after heating to 60-70°, acetone 
is added to the extent of one-third the volume of the water, and the mix- 
ture shaken for ten minutes; 5 mils of sodium hydroxide 10 per cent are 
added and the liquid shaken until the hydriodide has disappeared; the 
mixture is then diluted with three times its volume of water and allowed 
to stand overnight. The berberin-acetone is filtered off onto a Gooch 
crucible, dried first in a vacuum and then at 105° and weighed, 1 gram 
1 Arch. Pharm., 1901, 239, 638. 



■i 



ALKALOIDS DERIVED FROM ISOQUINOLIN 237 

of the compound corresponds to 0.853 gram of berberin. To correct for 
the berberin-acetone compound dissolved in the mother liquor 0.0000273 
gram is added per mil. 

In the event of the products containing berberin alone, or with oxyacan- 
thin and berbamin, the preliminary treatment of the sample will follow 
the procedure described above and the oxyacanthin and berbamin removed 
by shaking out with ether after rendering alkaline; the solution is then 
acidulated, the berberin precipitated with potassium iodide and the deter- 
mination completed by forming the acetone compound. 

Berberin may be determined titrimetrically by precipitating the hydro- 
chlorate with potassium-naphthalin thiosulphonate, and titrating the 
excess of thiosulphonate with N/100 iodine. 1 The thiosulphonate is 
added in excess to the solution of the alkaloid, the precipitate is filtered 
off, and the filtrate and washings titrated with the iodine. Each mil of the 
N/100 thiosulphonate solution corresponds to .003351 gram of berberin. 

Hydrastin is readily separated from morphin on account of its solu- 
bility in ether. In mixtures containing both alkaloids, after the pre- 
liminary treatment, a slight excess of fixed alkali is added and the hydras- 
tin removed by shaking out with ether; a little ammonium chloride is 
added and the morphin shaken out with chloroform-alcohol 2-1. 

ALKALOIDS OF THE CORYDALIS GROUP 

The Corydalis genus, Papaveraceae, embraces about 100 species, several 
of which have been employed in medicine. In our Materia Medica the 
term relates to the Turkey or Squirrel-corn, Bicuculla canadensis syn. 
Corydalis canadensis. The plant is small, resembling the common Dutch- 
man's Breeches (B. cucullaria) a closely related species, and has a yellow 
blossom and finely slashed leaves. It grows in moist, rich woods. The 
tubers, which constitute the drug, are small, roundish, with a slight peculiar 
smell, and a bitterish somewhat pungent and persistent taste. 

The drug is a tonic, diuretic, and slightly alterative, and in these par- 
ticulars resembles gentian, calumba, and other simple bitters. It has 
been employed in syphlitic, scrofulous, and cutaneous troubles, generally 
in the form of a liquid extract and with other drugs. It will be found in 
elixirs and syrups containing potassium iodide, Stillingia sylvatica, Xan- 
thoxylum americanum, and Iris versicolor; or with Stillingia, Iris, Chi- 
maphila umbellata (Pipsissewa or Prince's pine), Sambucus canadensis, 
Xanthoxylum berries, and coriander. 

The alkaloids of B. canadensis have not been carefully studied and 
hence we are uncertain whether or not they are the same as occur in 
Corydalis cava. Kraemer reports that they resemble the alkaloids of 
B. cucullaria, and that corydalin is one of them. 

1 Arch. Pharm., 1900, 238, 6. 



238 ALKALOIDAL DRUGS 

C. cava has been the source of practically all the material used in 
researches on these bases. The bulk of the work has been done by 
Gadamer, Ziegenbein, Dobbie and Lauder, and Makoshe and it will be 
given a brief summary here. 

Gadamer divides the alkaloids into three large groups and one of these 
is subdivided. 

I. Weak bases giving yellow berberin-like derivatives with alcoholic 
iodine 






Corydalin, C22H27NO4 m. 134-5° 

Cu H* ' Corybulbin. . (fad: .?}%/f/ m. 238-9° 

Isocorybulbin C21H25NO3 m. 179-80° 

II. Medium bases, not acted upon by alcoholic iodine. 

Corycavin, C23H23NO6 m. 216-17° 

Corycavamin, C21H21NO5 m. 149° 

III. Strong bases. 

1. Bulbocapnin, Ci7Hi3N(OCH 3 )(02CH 2 )OH m. 199° 

Corydin, Ci 7 Hi3N(OCH 3 )3(OH) 2 m. 103-5° 

Corytuberin, Ci 7 Hi3N(OCH3) 3 OH m. 240° 

2. Dicentrin. 
Glaucin. 

All of the above bases are removed from alkaline solution with ether 
except corytuberin, which is subsequently removed by chloroform. 

It is somewhat conflicting to place glaucin in a group of strong bases 
when it has been described among the Sanguinaria and Chelidonium alka- 
loids as a weak base, which can be removed from acid solution by chloro- 
form, but the author assumes no responsibility for Gadamer's grouping. 

Gadamer also reports protopin in the leaves of C. cava, and Heyl * 
reports its presence in the tubers of C. solida. 

Corydalin crystallizes from alcohol in prisms insoluble in alkalies, but 
somewhat soluble in water, and readily in organic solvents. When treated 
with iodine in alcoholic solution it is oxidized to dehydrocorydalin which 
closely resembles berberin. On reducing this substance, two isomeric 
inactive corydalins are formed, one melting 158-9° and the other 135°. 

To identify corydalin, Mulliken recommends the preparation of the 
nitrate, which melts with considerable ebullition from 193-200° C. The 
alkaloid is treated with dilute nitric acid (1-20) and well macerated. The 
liquid is carefully decanted, the residue dried on a porous tile, dissolved 
in a small quantity of boiling water, filtered hot, and the nitrate allowed 
to crystallize by spontaneous evaporation. 

1 Apoth. Zeit., 1910, 25, 36. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 



239 



Corybulbin may be separated from corydalin by dissolving the bases 
in hydrochloric acid, adding excess of sodium hydroxide which precipitates 
corydalin only, and after removing the latter, corybulbin is precipitated 
by carbon dioxide; or it may be separated by treating crude corydalin 
with hot alcohol until most of the corydalin is dissolved, and then boiling 
with a large quantity of alcohol, from which the corybulbin separates 
as a fine crystalline powder. It is nearly insoluble in water and ether, 
soluble with difficulty in alcohol and readily in chloroform. It can be 
converted into corydalin by treatment with equivalent quantities of methyl 
iodide and potassium hydroxide in methyl alcohol. It reacts with iodine 
to produce lemon yellow needles. 

The color reactions of some of the bases of this group are reported 
as follows: 



Reagent 


Corydalin 


Dehydro- 
corydalin 


Bulbocapnin 


Corycavin 


Corybulbin 


Sulphuric acid 


After some 
time red and 
violet 




Orange 
gradually 
violet-red 
violet. 


Dirty 
green- 
brown 
violet 




Nitric acid 


Yellow 


YeUow 


Reddish 
to brown 


Red 


Yellow 


Erdmann's reagent 


Yellow- 
green-vio- 
let 


Yellow- 
green- 
violet 


Blue-blu- 
ish violet 


Dirty 
green 


Yellow 


Froehde's reagent 


Yellow-pale 
green-blue 


Yellow- 
blue 


Dark blue 


Dark 
Green 


Red-brown 
green 


Sulpho-vanadic acid 


Yellow- 
green-blue 


Yellow- 
green-blue 


Bright 
olive-blue 


Dark 
green 


Brown- 
green 



The possibility of confusing an alkaloidal residue from Corydalis with 
one from Chelidonium must be emphasized. 



GELSEMIUM AND ITS ALKALOIDS 

Gelsemin, C20H22N2O2. 
Gelseminin. 
Semperviren. 
The rhizome of yellow jasmine or jessamine, Gelsemium sempervirens 
(Loganiacese) , official in the Pharmacopoeia, contains the first two alka- 
loids above mentioned, and possibly the third. 

In addition to the basic constituents, the drug contains about 4 per 



240 ALKALOIDAL DRUGS 

cent of resin, emodin monomethyl ether, ipuranol, scopoletin, the mono- 
methyl ether of aesculetin, both free and in the form of a glucoside, and 
some sugar. 

Gelsemium is antipyretic and antizymotic and induces paralysis of sen- 
sibility and motility. It is used in neuralgic conditions, for ague, malaria, 
and sometimes for treating the morphin and liquor habits. Morphin, 
alcohol, and to some extent atropin are physiologically antagonistic. 

The drug is offered in the form of its fluid, solid and powdered extracts, 
as a concentration " gelsemperin "; and the alkaloid gelsemin is employed 
in the form of the hydrochloride. 

Gelsemium is combined with the Cinchona alkaloids and Capsicum 
in ague pills; with arsenic and ferrous sulphate and sometimes with strych- 
nin and Podophyllum in malaria and periodic pills; with mercury and 
ipecac for desentery. In tablet form it occurs combined with acetanilid, 
caffein, and sodium bicarbonate; with acetanilid, camphor monobromate, 
sodium salicylate, and Hyoscyamus for migraine. It is combined with 
codein, acetanilid, caffein and bromides in elixirs, and also with coca. 
Gelsemin hydrochloride is sometimes administered in the form of hypo- 
dermic tablets. Some confusion exists as to the nomenclature of the 
Gelsemium bases and Merck's description of gelseminin really applies 
to gelsemin as it is known to English writers. 

Gelsemin 

This alkaloid crystallizes in white glistening prisms, melting 178°, 
readily soluble in ether, chloroform, and alcohol, and sparingly soluble in 
water. Its solutions are dextrorotatory. Its constitution has not been 
determined and it is only within recent years that Moore obtained a 
product sufficiently pure to establish its composition as C20H22N2O2. It 
is a strong base and is precipitated by the usual alkaloidal reagents. 

Mulliken gives the composition of this alkaloid as C22H26O3N2, with 
a melting-point of 160° when dried in a desiccator, ancL_172° when dried 
at the temperature of boiling xylol or toluol. 

When pure it dissolves in concentrated sulphuric acid without color; 
and on the addition of an oxidizing agent, an intense red or purplish-red 
color develops, passing gradually to blue or bluish green and finally to 
blue or green. As gelsemin is nearly always contaminated with more or 
less gelseminin, the color obtained with sulphuric acid alone is reddish 
or brown gradually changing to pink, and on heating purple and choco- 
late colored tints appear. The colors obtained on adding oxidizing agents 
to a sulphuric acid solution of an impure gelsemin are red to purple, with 
purplish-red streaks following the course of the oxidizing agent, finally 
becoming blue-green. If cereso-ceric oxide is used, the red coloration is 
very intense. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 241 

A solution of gelsemin in concentrated nitric acid reddens on warming 
and finally becomes dark green. The pure alkaloid dissolves in nitric 
acid with little or no color, and on allowing the liquid to evaporate spon- 
taneously, a permanent bluish-green color results". 

Gelsemin gives characteristic crystalline precipitates with gold and 
platinum chlorides, and a well-defined crystalline hydrochloride which 
is readily soluble in water but difficultly so in alcohol. Its solubility in 
alcohol is made available in separating it from gelseminin, as the hydro- 
chloride of the latter dissolves readily in this solvent. 

Pure gelsemin appears to have a very slight toxic action and the effects 
of the commercial preparations are thought to be due to the gelseminin, 
which may be present in varying quantities. 

Gelseminin 

Gelseminin is the name given to an amorphous basic substance which 
is also obtained from gelsemium. It is apparently a mixture of two or 
more alkaloids. 

Neither gelseminin nor its salts have been crystallized. The base 
gives the usual precipitates with alkaloidal reagents and resembles gel- 
semin in its color reactions. Physiologically it is a strong poison and 
much more active than gelsemin. It also produces mydriasis and mix- 
tures of strychnin and gelseminin might on analysis be mistaken for mix- 
tures of strychnin and belladonna. 

Semperviren 

This alkaloid may be obtained, according to Sayre x and Stevenson, 
by dissolving a mixture of the crude alkaloids in chloroform and completely 
extracting with 1 per cent hydrochloric acid. On saturating with sodium 
nitrate, the nitrate of semperviren- is thrown out, and may be separated 
and crystallized from hot alcohol. The free base recovered from the salt 
crystallizes in reddish brown needles, soluble in chloroform and alcohol 
and almost insoluble in ether, benzol, and petroleum ether. 

Scopoletin, C 9 H 5 3 OCH3 

Scopoletin is the principle of gelsemium which gives a blue fluores- 
cence with ammonia, and is a very useful substance in analytical work 
for establishing the presence of the drug. It is readily soluble in chloro- 
form from acid solutions, and on shaking the chloroform with dilute 
ammonia, the aqueous layer, on separation, will show a distinct blue 
fluorescence. 

1 J. Amer. Pharm. Ass., 1915, 1458. 



242 ALKALOIDAL DRUGS 

Scopoletin crystallizes from alcohol in long colorless needles, melting 
at 204° and subliming at 140-170°. It gives an acetyl derivative, melt- 
ing 177°. 

This substance has been called " gelseminic " acid and has also been 
mistaken for sesculin, the fluorescent substance from the horse-chestnut 
bark which does not sublime. 

Separation of the Alkaloids. — Stevenson and Sayre L in the reports 
of their researches on Gelsemium suggest a method for separating the 
alkaloids. The procedure in detail is as follows: the mixed alkaloids are 
dissolved in chloroform, which is shaken with several portions of 1 per 
cent hydrochloric acid, testing each portion with saturated sodium ni- 
trate, until a fraction is obtained which gives no precipitate with the 
reagent. The combined acid washings are treated with a sufficient quan- 
tity of the nitrate to remove the semperviren, and the nitrate is filtered 
off and washed with saturated sodium nitrate and then with a small 
quantity of distilled water. The filtered acid solution is preserved. 

The chloroform solution is then continously extracted with the 1 per 
cent acid until all of the alkaloids are removed, and this solution is com- 
bined with the filtered solution above mentioned. The acid solution is 
shaken with benzol and then with chloroform, several portions of each 
solvent being employed; after which it is rendered just neutral with sodium 
hydroxide, and evaporated to dryness at a low temperature. The residue 
is extracted with several small fractions of alcohol which dissolves the 
gelseminin hydrochloride and a portion of the gelsemin hydrochloride. 
The alcoholic solution is evaporated to a small volume and allowed to 
stand for some time when the major portion of the gelsemin hydrochloride 
will separate. After filtering the filtrate is mixed with sand, evaporated 
at a low temperature and extracted with acetone, which takes up the 
gelseminin hydrochloride. 

The free bases can be recovered from their salts by the usual methods 
of alkaloidal separation. 

Qualitative and Quantitative Testing. — The presence of Gelsemium as 
a drug either by itself or in a mixture is not difficult to establish; the 
scopoletin is readily detected, and following this, the identification of 
the bases makes the diagnosis complete. The alkaloids when alone may 
be identified without difficulty, the only substances for which they might 
be mistaken being strychnin and yohimbin, and they can be differentiated 
from these bases because a residue evaporated with nitric acid does not 
give a purple color with alcoholic potash. If, however, they occur con- 
jointly with the bases above mentioned their identity becomes a matter 
of considerable difficulty, and as has already been mentioned, a mixture 
of strychnin and the Gelsemium bases might be mistaken for one of strych- 
1 J. Amer. Pharm. Ass., 1915, 4, 1458. 






Mm 



ALKALOIDS DERIVED FROM ISOQUINOLIN 243 

nin and the belladonna alkaloids. The reason for this is due to the fact 
that strychnin gives a reaction similar to Vitali's test for atropin or hyos- 
cyamin, and the mixed Gelsemium bases produce mydriasis. 

To test for scopoletin and the alkaloids, the product under exami- 
nation, if a solid, should be extracted with alcohol, (if a liquid, the water 
should first be evaporated), the alcohol filtered off, evaporated, the residue 
taken up with dilute hydrochloric acid and filtered into a separator. The 
acid solution is then shaken out with chloroform, a portion of the solvent 
run into a test-tube and shaken with water containing a little ammonia; 
on separating the alkaline layer will show a bluish fluorescence if scopoletin 
is present. If it is desired to proceed further with the identity of scopo- 
letin the chloroformic solution should be washed with water, filtered, evapo- 
rated, and the residue crystallized out of alcohol, the product obtained 
subjected to sublimation at about 150° C, and the melting-point of the 
sublimate determined. The acid solution, after the removal of the 
scopoletin, is then rendered alkaline, extracted with ether, then with 
chloroform, and portions of the residue from each extraction tested with 
the several oxidizing mixtures, and the gold and platinum crystalline salts 
examined under the microscope to observe their characteristic forms in 
comparison with known specimens. 

In making a quantitative estimation of the amount of Gelsemium bases 
in a mixture, the preliminary manipulation is the same as the processes 
employed for identifying the alkaloids. After removing the scopoletin 
and other substances soluble in chloroform from an acid solution, the 
liquid is made alkaline and extracted with ether and chloroform, the sol- 
vents washed with water, run through a filter into a tared dish, evapo- 
rated and the residue weighed. If acetanilid and caffein have been found 
the acid solution must be thoroughly extracted with chloroform before 
rendering alkaline as these substances are both extracted from an alka- 
line solution. 

There are no satisfactoiy methods known at present for the separation 
of gelsemin and gelseminin from codein, strychnin, ipecac,' or cinchona 
alkaloids. 

ALKALOIDS OF THE CELANDINE AND BLOODROOT 

Chelidonin. 

Chelery thrin. 

Sanguinarin. 

a-Homochelidonin. 

/3-Homochelidonin. 

7-Homochelidonin . 

Protopin. 



244 



ALKALOIDAL DRUGS 



These alkaloids occur in the two drug plants, Chelidonium majus, 
garden celandine or tetterwort, and Sanguinaria canadensis, bloodroot. 
They also occur in Stylophorum diphyllum, Bocconia frutescans, Boc- 
conia cordata, and Eschscholtzia Calif ornica, all of the above plants 
belonging to the Papaveracese. Some of them are found in Adlumia 
cirrhosa, Fumaria officinalis, and Glaucinum corniculatum. 

In addition to the above mentioned alkaloids Schlotterbeck reports 
the presence of other alkaloids, all of which have been summarized in 
the following table. 

It is of special interest in our work to observe that Chelidonium does 
not contain sanguinarin and that Sanguinaria is free from chelidonin. 



ALKALOIDS 



Drug 


Sanguin- 
arin 


Cheleryth- 
rin 


Protopin 


Chelido- 
nin 


alpha- 
Horn o- 
cheli- 
donin 


beta- 
Horn o- 
cheli- 
donin 


gamma- 
Homo- 
cheli- 
donin 


Sanguinaria 

Chelidonium 

Stylophorum 

Adlumia 

Eschscholtzia 

Bocconia 

Glaucinum ....... 


Present 

Present 

Present 
Present 
Present 


Present 
Present 

Present 
Present 
Present 


Present 
Present 
Present 
Present 
Present 
Present 
Present 


Present 
Present 


Present 


Present 
Present 

Present 
Present 
Present 


Present 
Present 

Present 



Drug 


Stylopin 


Diphyllin 


Adlumin 


Adlumi- 
din 


Berberin 


Ionidin 


Glaucin 


Sanguinaria 

Chelidonium 

Stylophorum 

Adlumia 


Present 


Present 


Present 


Present 


Present 


Present 




Eschscholtzia 

Bocconia 






Glaucinum 




Present 



Chelidonium majus is a perennial herb, 1 to 2 feet high, growing along 
fences, roadsides, and in waste places, and the entire plant is used as the 
drug. It was formerly official in the U. S. Pharmacopoeia. 

Chelidonium is a drastic purgative and is also somewhat diuretic, 
expectorant, and sudorific. It has been used for cancer and its juice is 
employed externally for corns and warts and to subdue traumatic inflam- 
mation. However, it is not a drug that is in general use and will seldom 
be encountered in analytical practice. 

Sanguinaria canadensis is a perennial herb, about 6 inches high, grow- 
ing in rich open woods. 



ALKALOIDS DERIVED FROM ISOQUINOLIN 245 

Sanguinaria is used as a tonic, alterative, stimulant, emetic, and expec- 
torant, but is chiefly employed as a stimulant expectorant in bronchitis, 
croup, and asthma. The extract of the whole drug, a concentration 
representing the alkaloidal constituents, and alkaloidal sanguinarin in the 
free state and in the form of the nitrate and sulphate are all used in the 
compounding of galenical preparations. Extract of Sanguinaria is mixea 
with the extracts of Veronica virginica (leptandra), butternut, and Hyoscy- 
amus in liver pills; with extracts of Iris versicolor; Euonymus atropur- 
pureus (wahoo) and Podophyllum resin; with ammonium chloride and 
tartar emetic with and without opiates in croup mixtures and expecto- 
rants. 

Syrup Horehound compound usually contains the extracts of San- 
guinaria, Inula helenium (elecampane), Aralia racemosa (spikenard), 
Symphytum officinalis (comfrey), Prunus serotina (wild cherry), Mar- 
rubium vulgare (horehound), and Ceanothus Americanus (Jersey tea or 
red root). Fluid extract wild cherry compound used for making the 
syrup, contains Prunus serotina, Marrubium vulgare, Veratrum viride, 
Lactuca canadensis (wild lettuce), and Sanguinaria. Fluid extract Lobe- 
lia compound contains Lobelia inflata, Spathyema fetida (skunk cabbage), 
and Sanguinaria. White pine compound often consists of Sanguinaria 
and morphin acetate with Pinus strobus (white pine) bark, Prunus ser- 
otina, Aralia racemosa, sassafras, and balsam poplar buds. White-pine 
tablets may contain opium, potassium nitrate, camphor, methjd salicylate, 
Sanguinaria, ipecac, Polygala senega, squills, Primus serotina and Pinus 
strobus. Anodyne expectorants consist of about the same ingredients 
as white-pine syrup, and often contain chloroform in addition. San- 
guinaria with coltsfoot, Glycyrrhiza, and demulcents are combined in 
throat lozenges. 

The fluid extract of Sanguinaria is made with acetic acid as a men- 
struum, a point which should be borne in mind in case of a controversy 
over the presence or absence of extract of Sanguinaria in a liquid product. 

With the exception of Chelidonium and Sanguinaria, the other plants 
containing the alkaloids under consideration have seldom been used in 
the composition of medicines, but their possibilities are attractive and 
there is no reason why they should not appear in proprietary mixtures. 

Sanguinarin is generally regarded as the most important constituent 
from a medical point of view, though the percentage of chelerythrin in 
the drug is considerably greater. 

Sanguinarin, C20H15NO4 

Sanguinarin crystallizes from chloroform with a melting-point of 212°. 
It is a white base, insoluble in alkalies, and gives intense red salts. It 
is probable that the molecule varies with the medium from which it crys- 



246 ALKALOIDAL DRUGS 

tallizes and contains a portion of the solvent in its composition. It is 
but slightly soluble in petroleum ether, but dissolves readily in ether and 
chloroform. It gives precipitates with the usual alkaloidal precipitants 
and is indicated in the general scheme of alkaloidal analysis, when a resi- 
due, tested with Mayer's reagent, gives a red precipitate. 

It gives a red color w T ith sulphuric acid; an orange with nitric; an 
orange to scarlet with Erdmann's reagent; carmine to dirty brown with 
Froehde's; and dark green to violet brown with vanadium-sulphuric acid. 
The pure base dissolves in ether to a colorless solution and yields a bright- 
red precipitate of the hydrochloride when treated with hydrochloric 
acid gas. 

Its salts are commercial articles and are probably impure, containing 
a considerable proportion of the other bases. 

In the drug it is probable that the greater part of the alkaloid present 
is not in the form of a salt of the free base, but as a more stable compound 
whose salts are red in color and yield the base on hydrolysis. 

Chelerythrin, C0H17NO4 

This alkaloid crystallizes from solvents with a molecule of the mother 
liquor from which it is freed only with difficulty. It separates from a 
mixture of alcohol and acetic ether in colorless crystals containing 1 mole- 
cule of alcohol, melting 203-204°; when crystallized from toluol it melts 
257° and on drying at 100° it loses 10-11 per cent by weight giving off 
the odor of the solvent. 

It has a distinct pink tinge when viewed en masse. When dissolved in 
chloroform the solvent is fluorescent, but the fluorescence seems to dis- 
appear with increased purity. It gives bright-yellow salts with acids, and 
those with mineral acids are but sparingly soluble in excess of acid. It is 
freely soluble in chloroform but only sparingly in ether. 

With strong acids and Erdmann's reagent a deep-yellow color is 
obtained, with Froehde's reagent yellow to dirty green, and with vana- 
dium-sulphuric acid red to violet. 

A solution of chelerythrin in 95 per cent alcohol or in a mixture of 
alcohol and chloroform, when treated with carbon bisulphide containing 
iodine, gives a ruby red periodide, melting 225°. 

It forms a compound with gold chloride which separates from alcohol 
in brown needles, melting 233° with decomposition. 

Chelidonin, C20H19NO6 

Chelidonin forms crystals containing 1 molecule of water, melting 135- 
136°. The crystals when warmed or rubbed produce a cracking sound 
accompanied by the emission of light, visible in a darkened room. It is 



ALKALOIDS DERIVED FROM ISOQUINOLIN 247 

dextrorotatory. Its hydrochloride is sparingly soluble and separates in 
crystals when hydrochloric acid is added to a solution of the sulphate. 
Gold chloride yields an orange-red precipitate which crystallizes violet- 
red from alcohol. The platinochloride is yellow, and melts 155°. The 
periodide is light red and black. 

When a solution of guaiacol in sulphuric acid is sprinkled with cheli- 
donin a carmine-red color is produced. Nitric acid added to a solution 
of the base in sulphuric acid gives a green color. Sulphuric acid alone 
produces a yellowish or orange color changing to violet; Erdmann's reagent 
gives a greenish yellow turning to violet; Froehde's reagent gives bluish 
green; vanadium-sulphuric acid gives green turning to blue green. 

It forms a benzoyl derivative which melts at 217°. 

Homochelidonin, C21H23NO5 
/3-Homochelidonin crystallizes in clusters or rosettes of boat-shaped 
crystals, melting 159°. It gives a rose-pink color with sulphuric acid, 
intensified by vapors of nitric acid; a yellow color with nitric acid; a 
yellow to violet with Erdmann's reagent; Froehde's reagent produces a 
play of colors brown at first, then violet, blue, green and yellow; vanadium- 
sulphuric acid gives violet, greenish blue to brown. 

It is soluble in the ordinary organic solvents. When crystallized from 
acetic ether it melts 169° and corresponds to 7-Homochelidonin. The 
form seems to depend on the solvent from which it is crystallized. Both 
forms give a blood-red aurochloride which crystallizes from alcohol in 
warty crystals, melting 187°. 

The alpha-form of this alkaloid melts 182°. 

Schlotterbeck's * description of the new alkaloids of Stylophorum 
diphyllum and Adlumia fungosa may be summarized as follows: 

Stylopin, C19H19NO5, melting 202°, (o)d-315 12' in alcohol, is almost 
insoluble in hydrochloric acid and insoluble in dilute sulphuric acid, which 
serves as a means of separating it from chelidonin. It is soluble in glacial 
acetic acid, from which concentrated hydrochloric acid precipitates fine 
needles of the hydrochloride. The nitrate separates from aqueous solu- 
tions in clusters of needles which appear almost jelly-like en masse. Pre- 
cipitates are obtained with the usual alkaloidal reagents, including bro- 
min water, potassium iodide, picric acid, and bichromate. 
L~ Diphyllin, melting 216°, accompanies chelidonin and may be sepa- 
rated from it by fractional crystallization from ether. It gives the follow- 
ing color tests; nitric acid yellow, violet to carmine red, then dull green 
to reddish brown; Erdmann's reagent, yellowish green to bright green; 
Froehde's reagent, deep green, olive green to olive; Marquis' reagent, vio- 
let to wine red. 

1 J. Amer. Chem. Soc, 1902, 1; Ibid., 1903, 596. 



248 ALKALOIDAL DRUGS 

Adlumin, melting 188°, {ajD-r 39° 88 , gives an amorphous precipitate 
with gold chloride which may be crystallized out of water. It is not 
precipitated by platinic chloride. With sulphuric acid it gives a lemon- 
yellow color; with nitric acid lemon to orange; Erdmann's reagent, olive 
green, brown to red; Marquis' reagent, light yellow to lavender. 

Adlumidin, melting 234°, crystallizes in square plates usually yellow 
in color but white when pure. Sulphuric acid produces bright red, olive 
brown to pink; nitric acid orange to light yellow; Erdmann's reagent 
brick red, greenish to brown; Marquis' reagent, bright red. dark brown 
to purple. 

Schlotterbeck also reports an unnamed alkaloid from Adlumia, melting 
176-177°, giving with sulphuric acid light yellow; Erdmann's reagent 
olive, brown to wine red; and no color with Marquis' reagent. 

GLAUCIN 

This alkaloid crystallizes from ether in pale yellow tablets, dextro- 
rotatory, melting 119-120°. It is a weak base and may be extracted 
from its acid solutions by chloroform. Its salts are fairly permanent and 
it is precipitated by the usual alkaloidal reagents. 

Recognition of Sanguinaria and Chelidonium. — The presence of san- 
guinarin may be suspected in the general scheme of alkaloidal analysis 
when the acid solution shows a pronounced red color. Aloes will often 
give a red color to a solution, but this drug has an unmistakable odor 
which is always prominent. If the red color disappears when the solu- 
tion is made alkaline and a white substance separates, insoluble in the 
alkaline liquid but dissolving in ether or chloroform, the worker may be 
reasonably sure of sanguinarin, and the evidence is further strengthened 
if a fluorescence is imparted to a chloroformic solution. The residue left 
on evaporating the solvent should be dissolved in absolute ether and 
treated with a stream of dry hydrochloric acid gas which will produce a 
precipitate of the bright red hydrochloride of sanguinarin. 

Chelerythrin follows sanguinarin closely in its solvent properties, and 
therefore a residue obtained in medicinal analysis will generally contain 
both alkaloids. This fact will modify the results obtained in performing 
color tests and unusual results must not be taken as negative indications. 
The color tests reported under the descriptions of the individual bases 
have been taken from the reports of the researches on the respective sub- 
stances, but they must not be considered as absolutely correct. The 
alkaloids of this group have not been subjected to the same degree of care- 
ful investigation as those of some of the other drugs and until further 
research has been performed much of the data must be taken with reserve. 

The separation of sanguinarin from chelerythrin has been effected by 



■u 



ALKALOIDS DERIVED FROM ISOQUINOLIN 249 

Kozniewski x who took advantage of tne difference in solubility of their 
sulphates, but such a procedure is of little use in our work owing to the 
limited amount of material available in any one sample. 

If the analyst is presented with a cough lozenge which presumably 
contains a large percentage of demulcent substances, and which he wishes 
to test for sanguinarin, the simplest procedure consists in grinding as 
many lozenges as can be spared and extracting them directly with ether. 
The ether solution will contain the bases with but little contaminating 
material and the pure alkaloids can then be extracted with dilute sul- 
phuric acid and recovered from the acid solution by adding ammonia 
and shaking out with ether or chloroform. 

The mixtures containing sanguinarin are of such a nature that the 
identity of the alkaloid is not difficult to determine. 

Kozniewski, Anz. Akad. Wiss. Krakan, 1910. Reihe, A. 235, J. Chem. Soc, Abst., 
1910, 874. 



CHAPTER VIII 

ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN 

NUCLEUS 

THE STRYCHNOS ALKALOIDS 

Strychnin, C21H22N2O2. 
*/ Brucin, C23H26N2O4. 

Strychnicin. 

Tubocurarin, C19H21NO4. 
v^ Curin, C18H19NO3. 
^ Curarin, C19H26N2O. 

Protocurin, C20H23NO3. 

Protocuridin, C19H21NO3. 

Protocurarin, C19H23NO2. 

Strychnin is found in the seed and pulp of Nux Vomica, Strychnos Nux 
Vomica (Loganiacese) , in the bark of the same plant " false Angostura 
bark," and in the seeds of Strychnos ignatia " St. Ignatius Beans." It 
also occurs in the root and wood of S. *columbrina L., snakewood tree; in 
the seeds and roots of S. tieute " deadly upas-tree," the root extract of 
which is employed in the preparation of a poison known as Upas Tieute 
or Upas Radja; and in the bark of S. malaccensis, known as Hoang-Nan. 

Brucin accompanies strychnin in all the above plants, but the seeds 
of S. rheedii contain brucin alone, and according to Bruhl S. ligustrina 
contains 2.26 per cent brucin, but no strychnin. Strychnicin is claimed 
by Boorsina to occur in the leaves of S. Nux Vomica. 

The other alkaloids are found in Curare, the dark resinous extract of 
several species of Strychnos, particularly of S. toxifera and S. castetuaca. 

The pulp in which the Nux Vomica seeds are imbedded contains when 
dry about 5 per cent of loganin, a crystalline glucoside. 

The extreme bitterness of the Strychnos bark, its twisted appearance, 
the impossibility of separating it into thin layers, and the blood-red color- 
ation produced on applying nitric acid to the internal coat are characters 
by which it is easy to distinguish it from the true Angostura bark. 

The Nux Vomica of commerce comes principally from India, Ceylon, 
Cochin-China, and Northern Australia. The Ceylon seeds contain from 

250 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 251 

4.4 to 5.4 per cent of the mixed alkaloids, those from Bombay 3.2 per 
cent, from Cocriin-China 3 per cent, from Madras 2.75 per cent. The 
amount of strychnin is a little less than half. The alkaloids are com- 
bined with igasuric (" strychnic "j acid, which appears to be identical 
with chlorogenic acid. 

Preparations containing Nux Vomica or its alkaloids are used for 
general tonic purposes, and the principles often occur in remedies for 
neuralgia, impotence, neurasthenia, constipation, and cardiac troubles. 
Ignatia and Hoang-Nan containing the same constituents as Nux Vomica, 
are used for the same purposes though to a very hmited extent compared 
with Nux Vomica. 

Pills and tablets of Nux Vomica or of strychnin are many and varied 
as to their composition. The anti-constipation formulas employ aloes and 
strychnin, or aloin, belladonna, and strychnin, combined with one or more 
of the following: Cascara, ipecac, rhubarb, Podophyllum, Capsicum, 
Hyoscyamus, gentian, and jalap. Anti-malarial compounds contain 
strychnin with iron, quinin, arsenic, aloes, Hyoscyamus, Capsicum, or 
bismuth subnitrate. With ipecac, belladonna, colocynth, mercury, sodimn 
bicarbonate, often with pepsin and sometimes with iron and bismuth sub- 
nitrate it will be found in anti-dyspeptic mixtures. Carminatives con- 
tain strychnin with ipecac, gentian, and black pepper. With Cactus 
grandiflorus, spartein, digitalin, nitroglycerin, and strophanthin, it enters 
into the composition of heart tonics. 

Combinations of strychnin, irisin, Podophyllum, and Hyoscyamus 
are not uncommon. Iron, arsenic, and strychnin is a common formula, 
and this is often combined with quinin salts, with ipecac, aloes, gentian, 
cascara, creosote, and various hypophosphites, the different combinations 
being used as tonics. Neuralgics will contain strychnin, aconitin, quinin, 
and arsenic occasionally, with the addition of morphin, zinc phosphide, 
and Cannabis sativa. The so-called nerve tonics, aphrodisiacs, " restor- 
ers " and the like, contain strychnin in combination with phosphorus, 
cantharides, zinc salts, iron compounds, often with aloes, quinin, damiana, 
and gold and sodium chloride. Certain " sedatives " contain strychnin, 
valerianates or valerian, cocain, codein, arsenic, Cannabis sativa, and iron 
salts. 

Among the liquid products strychnin will be found in a number of 
combinations usually in the form of elixirs, the more important being 
general tonics, aphrodisiacs, heart tonics, and digestants. These will con- 
tain in addition to strychnin, various proportions of Cinchona alkaloids, 
iron salts, bismuth, and ammonium citrate, pepsin, aloin, Podophyllum, 
and belladonna; phosphorus and damiana; and Digitalis, Strophanthus, 
and nitro-glycerin. The " Hypophosphite " and " Phosphate " class of 
syrups nearly always contain strychnin combined with phosphates or hypo- 



252 ALKALOIDAL DRUGS 

phosphites of potassium, sodium, magnesium, calcium, manganese, iron, 
quinin, and free phosphoric acid. 

Capsules of strychnin with cresote, codliver oil, atropin, and arsenous 
acid are used medicinally. 

Malt products often contain strychnin in combination with quinin. 

Preparations of ignatia are few, but it occurs in a pill and tablet formula 
used as an anti-neuralgic, where it is combined with opium, Hyoscyamus, 
belladonna, Conium, stramonium, aconite, and Cannabis sativa. It is 
also sold in liquid and tablet form combined with phosphorus, Cinchona, 
gentian, Calumba, and Nux Vomica. 

The curare alkaloids are used occasionally for anti-tetanics and nerve 
stimulants. 

Strychnin 

Strychnin occurs in the form of colorless, transparent, prismatic crys- 
tals or a white crystalline powder, anhydrous, odorless, permanent in the 
air, and having an intensely bitter taste. It is a tertiary, monacid base, 
extremely poisonous, and should be handled with caution. 

From the results of experiments conducted by Claus and Glassner x 
it would appear that the strychnin of commerce is not always of the same 
composition, in some instances corresponding to the formula C22H22N2O2 
and in others to C21H22N2O2. It was apparent from this work that com- 
mercial strychnin probably contained homostrychnin, C22H24N2O2. 

The melting-point is variously given from 265° to 269°. It will dis- 
till without decomposition at a pressure of 5 mm. 

It is readily soluble in chloroform and hot alcohol and fairly soluble 
in benzol and amyl alcohol, much less in ether and with difficulty in water 
and petroleum ether. The latter solvent will, however, remove strychnin 
from a solution made alkaline with ammonia. 

Strychnin solutions are lsevogyrate and alkaline in reaction. 

Concentrated sulphuric acid, Erdmann's and Froehde's reagents, dis- 
solve strychnin without color. Its solution in nitric acid becomes yellow. 
It is readily soluble in dilute acids. On heating with concentrated sul- 
phuric acid, at 100°, a sulphonic acid of strychnin is produced which gives 
very insoluble precipitates with the alkali and alkaline earth metals and 
also with lead and copper. 

Solutions of strychnin are precipitated by ammonia and the alkalies, 
but not by sodium bicarbonate. Strychnin is not very soluble in solu- 
tions of the alkalies, but dissolves somewhat easily in ammonia. 

Strychnin forms a number of well-defined salts, some of which are 
readily soluble in water, while others are very insoluble. Most of the 

1 Berichte, 14, 773. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 253 

salts are soluble in alcohol but are insoluble in the other ordinary organic 
solvents. The hydrochloride, hydrobromide, nitrate, sulphate, acid sul- 
phate, and acetate, dissolve in water without great difficulty. The hydro- 
iodide is only sparingly soluble, while very insoluble and characteristic 
precipitates are obtained with potassium chromate, ferrocyanide and 
ferricyanide, mercuric chloride, sodium phospho-molybdate and phos- 
photungstate, potassium bismuth iodide, potassium-mercuric iodide, 
iodine, platinic and gold chlorides, tannic and picric acids; and the vary- 
ing solubilities of the isomeric salts have been of great value in the develop- 
ment of the chemistry of tartaric acid and other acids having stereoiso- 
meric modifications. It also forms a compound with sulphide of hydro- 
gen when treated in alcoholic solutions with this reagent or with alcoholic 
yellow ammonia sulphide. 

The precipitate obtained with potassium-bismuth iodide is one of the 
most insoluble combinations, closely followed by the chromate, ferrocy- 
anide, mercurochloride, phosphotungstate, phosphomolybdate, and mer- 
curoiodide. The reactions with ferrocyanide and chromate are of value 
in separating strychnin from brucin, and the ferrocyanide reaction has 
been employed quantitatively. 

The precipitate formed with a solution of iodine in alcohol resembles 
herepathite, the product of similar nature given with quinin. Strychnin 
is removed from an aqueous solution by animal charcoal. 

The color reactions of strychnin are extremely sensitive and important 
as a means of identifying the alkaloid. When dissolved in concentrated 
sulphuric acid and treated in the cold with an oxidizing agent a purple 
color develops, more or less fleeting, depending on the quantity of the alka- 
loid and the particular agent employed, and which finally becomes pale 
cherry-red. Potassium bichromate probably has been employed as an 
oxidizing agent to a greater extent than any other. Allen prefers man- 
ganese dioxide, and other substances, ammonium vanadate, cerosoceric 
oxide, potassium ferricyanide have been highly recommended. The play 
of colors depends on the quantity of material present. With sufficient 
of the alkaloid, the full change from blue to purple, purplish-red, cherry 
red, and finally yellow, will be noted, but when the amount is small a 
purple changing rapidly to yellow will be the only marked characteristic. 
When the quantity is very small it is advisable to dissolve the oxidizing 
agent in the acid before adding the latter to the residue under examination. 

This reaction, while very characteristic of strychnin, is unfortunately 
given in similar manner by other drug products which are extracted from 
alkaline solutions under the same conditions that strychnin would be with- 
drawn, and while in large amount there might be differences in the reac- 
tion sufficient to show wherein the product was not strychnin, there would 
always be a doubt, especially in forensic work, unless fully substantiated 



254 ALKALOIDAL DRUGS 

by other tests, and when the quantity was small the difficulty of differ- 
entiating would be well nigh impossible. 

Some substances give colors with sulphuric acid alone, codliver oil 
being one which, when pure, produces a beautiful display of shades, from 
purple through crimson, to brown. Certain glucosides and other prin- 
ciples produce colors, but most of them are removed from acid solution 
by immiscible solvents. Anilin is stated to give with sulphuric acid and 
oxidizing agents a green color, changing to blue and eventually becoming 
black. Allen states that colocynth resin gives a very similar reaction to 
strychnin, but is removed by agitating the acidulated solution with benzol 
or ether. The writer found, however, that when working with an extract 
of colocynth, sufficient material remained in solution after previously 
shaking out the acid liquid with immiscible solvents, to appear later in 
the residues obtained by shaking out the alkaline solution and give a pur- 
ple tint with sulphuric acid and oxidizing agents. The reaction in this 
case, however, in no way resembled that obtained with strychnin, for a 
dirty color first appeared and after several minutes a purple shade was 
apparent in thin layers. 

It has been shown that residues obtained by shaking out alkaline 
solutions of the following drugs with immiscible solvents give a purple 
reaction with sulphuric acid and bichromate, namely, Gelsemium, Hy- 
drastis, opium, Sanguinaria, and yohimbe. The similarity in the reactions 
of strychnin and yohimbin is of interest, as the drug containing the latter 
alkaloid has of late been exploited as a remedial agent for the same pur- 
poses that strychnin has been used. It has been claimed to possess aphro- 
disiac properties and might be suspected in mixtures advertised for tonics 
and the like. When working with small quantities the reactions are so 
much alike that one could form no conclusion as to which alkaloid was 
present. In larger amount the yohimbin gives a purple, changing to 
reddish and then to olive green and in still larger amount the color is 
first an indigo blue. The reaction with ammonium vanadate, however, 
is so nearly identical with that given by strychnin that no distinction 
can be drawn with any safety. However, yohimbin forms very few salts 
which have any characteristic form under the microscope, while those 
given by strychnin are well defined and can be distinguished readily, and 
furthermore its physiological action is different. There is little danger 
of confusing strychnin with the principle of colocynth, which gives the 
purple color with sulphuric acid and bichromate, and as regards the alka- 
loids of Hydrastis, Gelsemium, and Sanguinaria, which act similarly, none 
gives the purple color with nitric acid and alcoholic potash subsequently 
described, and there are a number of distinctive characteristic reactions 
for these substances which are fully described under their respective 
headings. With ammonium vanadate, berberin gives a red, soon chang- 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 255 

ing to plum-color, and gelseminin a magenta, changing to blue green. 
The purple color given by the opium alkaloids would hardly be mistaken 
for that given by strychnin, as it is very lasting. It was found on inves- 
tigation that narcein and papaverin were the two alkaloids giving the 
purple tint, no similar reaction being obtained with thebain, narcotin, 
codein, or morphin. Curarin gives virtually the same color reaction as 
strychnin, and a ptomain has been described giving a similar oxidation 
test. 

In small proportions brucin exercises no injurious influence on the 
oxidation test for strychnin, but when much is present it interferes in a 
marked manner. Hence it is safest to separate the strychnin first as 
chromate or ferrocyanide by precipitation and after filtering to examine the 
solution for brucin. Another method directs the solution of the substance 
in concentrated sulphuric acid, adding a trace of nitric acid or potassium 
nitrate and waiting until the red color changes to yellow, when a crystal 
of potassium bichromate will give the characteristic strychnin reaction. 

The writer has obtained good results by shaking out the alkaline solu- 
tion two or three times with petroleum ether and testing the residue left 
on evaporation of the solvent, for strychnin. Then on shaking out with 
chloroform the brucin will be removed and may be identified by testing 
the residue on evaporation. 

Strychnin when evaporated with concentrated nitric acid leaves a 
yellowish residue which becomes a beautiful purple on treatment with a 
few drops of alcoholic potash, the reaction being very similar to that 
given by atropin. In connection with this test, it is of interest to note 
that yohimbin gives the same reaction. When working with extract of 
Nux Vomica it was found that only the alkaloidal portion removed by 
petroleum ether would give the purple color on adding the alcoholic pot- 
ash, for the red color produced by the nitric acid on the brucin masked 
the purple tint given by the strychnin. Extracts from coca leaf and 
Colchicum have been found to give purple colorations when this test was 
applied. 

Buchbinder has developed a color reaction which is very character- 
istic and little affected by impurities. The reaction is based on a test 
first published by Malaquin and then studied. by Deniges. Zinc amalgam 
is prepared by treating granular zinc with a little concentrated hydro- 
chloric acid to clear the surface. The acid is poured off and the metal 
covered with 1 per cent solution of tartar emetic, shaking occasionally 
during one hour, 1 mil of saturated solution of mercuric chloride is added 
for every gram of zinc, followed by a few drops of concentrated hydro- 
chloric acid, and after one-half hour the solution is poured off, the zinc 
washed and dried. To the dry alkaloid or to 0.5 mil of an aqueous solu- 
tion, 0.5-1 gram of the zinc amalgam is added followed by 0.5 mil con- 



256 ALKALOIDAL DRUGS 

centrated hydrochloric acid. After ten to twenty minutes the solution 
is poured from the zinc, a few drops of 0.02 per cent potassium ferrocy- 
anide solution added, when a color varying from pink to rose red is pro- 
duced. 

There are a number of other color reactions reported for strychnin, 
and their use subsequent to the others above mentioned are of value in 
differentiating stiychnin from those substances which give the oxidation 
tests. 

When treated with nitric acid and potassium chlorate after warming, 
an intense scarlet coloration is produced. This is changed to brown on 
adding ammonia, and on evaporation to diyness a dark green residue is 
left, soluble in water with a green color, changed to orange-brown by 
caustic potash and becoming green again on adding nitric acid. 

Zinc chloride gives a scarlet reaction with strychnin. A dry residue 
is moistened with a solution of 1 gram of melted zinc chloride in 30 mils 
of water and dried again. Brucin prevents the formation of the scarlet 
color, a dirty-yellow color developing. Veratrin will also give a red color 
and delphinin a red-brown. 

The appearance of the salts of strychnin under the microscope fur- 
nishes one of the most conclusive means for identifying this alkaloid. 

Gelseminin, which also gives an oxidation reaction similar to strychnin, 
has the same physiological action on the frog. 

Brucin 

Brucin is very similar to strychnin, and like the latter is a monacid, 
tertiary base. It contains two methoxyl groups, while strychnin con- 
tains none, the difference in the molecular weight of the two bodies cor- 
responding to the difference in their two methoxyl groups. On this account 
and from other data deduced from a study of the oxidation products, it 
appears that brucin is the dimethoxy-derivative of strychnin. 

Commercially it may be prepared by taking advantage of the insolu- 
bility of its oxalate in absolute alcohol, the oxalate of strychnin being 
dissolved; or the mixed alkaloids may be treated with cold absolute alco- 
hol or acetone which dissolves the brucin readily, leaving most of the 
strychnin behind. The commercial product has been claimed to consist 
of two homologous alkaloids. 

Brucin crystallizes from water with two or four molecules of water, 
ordinarily four, forming monoclinic prisms or shining leaflets, white, odor- 
less, and very bitter. From alcohol it is stated to crystallize with two 
molecules of water. The crystals melt in their water of crystallization 
when heated a little over 100° C. and the anhydrous base dried at 150° 
melts at 178° C. It is lsevorotatory. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 257 

It is much more soluble in water and alcohol than strychnin, dissolves 
readily in chloroform and benzol, somewhat soluble in ether. Allen claims 
that it will dissolve in 120 parts of petroleum ether, while the writer has 
found that in shaking out an alkaline solution of the mixed bases some of 
the strychnin will be removed by the petroleum ether, leaving the brucin 
behind. This, however, may be due to the greater solubility of the brucin 
in water. It is much less poisonous than strychnin, the physiological 
activity of the latter having been variously estimated as being 10 to 38 
greater than that of brucin. It is a weaker base than strychnin, but forms 
a number of well-defined salts. The hydrochloride, hydroiodide, nitrate, 
and sulphate are all soluble in water. The chromate and ferrocyanide 
are much more soluble than the corresponding strychnin compounds and 
are of value in effecting a separation of the two alkaloids. The ferricy- 
anide and hydrochloroplatinate are characteristic compounds showing 
well-developed forms under the microscope, and heavy precipitates are 
obtained with iodine-potassium iodide, potassium mercuric iodide, potas- 
sium bismuthous iodide, tannic and phosphomolybdic acids. When a 
solution of brucin in absolute alcohol is treated with alcoholic ammonium 
sulphide containing dissolved sulphur a product is formed having the 
composition (C22H2gN204)2H2Ss2H20, which may be obtained as orange- 
red crystals. 

Brucin is of value in separating racemic acids as it forms salts having 
different solubilities. 

Brucin does not resemble strychnin in its action with sulphuric acid 
and oxidizing agents. Pure sulphuric acid dissolves it without color, while 
the presence of a trace of nitric acid produces a reddish tint. 

On adding concentrated nitric acid in the cold to a brucin residue a 
scarlet or blood-red coloration is produced which on heating changes to 
yellowish red and finally to yellow. On adding a few drops of freshly pre- 
pared dilute stannous chloride solution, an intense violet color will appear, 
which changes again to yellow or red on heating, and again reappears on 
the addition of more stannous chloride. To perform this test success- 
fully the amount of nitric acid used should be small. Mauch claims to 
obtain excellent results by a modification of this test in which the brucin 
is dissolved in a 60 per cent aqueous solution of chloral hydrate. A small 
quantity of the mixture, about 0.5 mil, is placed in a test-tube and a few 
drops of nitric acid added and the whole shaken and poured carefully 
onto the surface of about 2 mils of concentrated sulphuric acid, when 
a yellowish-red or deep red zone, depending on the quantity of brucin 
present, will develop. As soon as the upper layer becomes yellow, stan- 
nous chloride is cautiously added by means of a pipette in order to form 
a top layer and on the dividing line an intense violet zone will form. 
The stannous chloride solution recommended consists of 1 part 



258 ALKALOIDAL DRUGS 

stannous chloride in 9 parts hydrochloric acid having a specific gravity 
of 1.12. 

The orange color produced by adding nitric acid to morphin remains 
unchanged on the addition of stannous chloride. 

If the cold nitric acid be added to solid bmcin so as to develop the 
color, and the mixture then largely diluted with water, a body called 
kakotelin separates in yellow flocks. The filtered liquid, after neutral- 
ization by ammonia, gives a precipitate of calcium oxalate on treatment 
with calcium chloride. The precipitated kakotelin may be dissolved in 
dilute hydrochloric acid and crystallized therefrom in orange-red or yellow 
scales. Its composition is C2oH22(N02)2N205. 

Potassium bichromate throws down from solutions of brucin salts a 
yellow precipitate of brucin chromate which is insoluble in acetic acid, 
but soluble in nitric acid with a red color. 

Mercurous nitrate added to an aqueous solution of a brucin salt pro- 
duces no change, but on warming a carmine color appears. 

A residue obtained on evaporating a solution of brucin in concentrated 
nitric acid will change to grass green on the application of fumes of ammonia 
gas, and the green product dissolves in hydrogen peroxide with formation 
of a violet color. This test, however, is not delicate in the presence of 
strychnin. 

The red coloration produced by brucin in the presence of nitric acid 
is of value for the detection of nitric acid or nitrates in water. A drop 
of the water in question is treated with several drops of brucin solution 
in water (1-2000), several drops of hydrochloric acid then added and 
shaken after the addition of a few mils of sulphuric acid. In the presence 
of a nitrate a rose to a red color develops, quickly changing to yellow. 

Brucin forms a number of well-defined derivatives. 

On passing nitrogen trioxide into an alcoholic solution of the alkaloid, 
brucin nitrate at first separates, but again dissolves, forming a red solu- 
tion, from which dinitrobrucin, C23H24(NC>2)2N204, separates as a heavy, 
granular, blood-red precipitate. By washing with alcohol and ether, it 
is obtained as an amorphous, velvety vermilion-colored powder, easily 
soluble in water, sparingly soluble in alcohol, and insoluble in ether. 

Separation of Strychnin for Purposes of Identification. — If the sub- 
stance is a solid, extract with 95 per cent alcohol; if a liquid, first evapo- 
rate the water, and then extract with the alcohol. Evaporate the solu- 
tion until the alcohol has been driven off. Digest the residue with normal 
sulphuric acid and filter into a separator; add ammonia in excess and 
shake out three times with Prolius mixture. Filter the combined por- 
tions of the solvent and evaporate over the steam-bath. Dissolve the 
residue in normal sulphuric acid, pour the solution into a separator and 
shake out first with chloroform and then with low-boiling 40-50° petro- 



M 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 259 

leum ether, discarding the solvents. Add excess of ammonia to the aque- 
ous solution and shake out three times with petroleum ether. Collect 
the solvent in another separator, wash with water, filter, and evaporate 
over the steam-bath. The petroleum-ether residue yields a strychnin of 
great purity, practically free from brucin. 

Quantitative Determination of Strychnin and Brucin. — If a medicinal 
agent contains no other alkaloid-bearing drug than Nux Vomica, nor any 
alkaloid except strychnin the determination of the amount present is 
attended with little trouble other than attention to details in the manipu- 
lation and possibly special treatments depending on the other ingredients. 

If the product contains but a small amount of solid material and no 
gum or emulsifying substances, the alkaloids may be removed by shaking 
out the ammoniacal solution with chloroform at least three times after 
first driving off any alcohol. If both strychnin and brucin are present 
the two may be separated and determined by the nitric acid process as 
described in the assay of Nux Vomica. This method is simpler and prob- 
ably more accurate than the ferrocyanide process recommended by earlier 
workers. 

If the residue left on evaporating the chloroform contains no brucin 
it should be dissolved again in dilute sulphuric acid, the solution shaken 
out with ether and chloroform, then rendered ammoniacal and the strych- 
nin removed by chloroform. 

The principal alkaloidal drugs which are used in combination with 
Nux Vomica include belladonna, coca, ipecac, Conium, and Stramonium, 
the two latter but seldom. The same drugs will be found in products 
containing strychnin alkaloid and in addition strychnin may be combined 
with quinin, morphin, aconitin, hyoscyamin, and spartein. 

The Nux Vomica alkaloids may be separated from the coca bases by 
dissolving the weighed residue of both in dilute hydrochloric acid and 
subjecting the mixture to the heat of the steam-bath for four hours in a 
digestion flask. The solution should then be shaken out with ether and 
chloroform, ammonia added in excess and the strychnin and brucin removed 
by chloroform. 

Strychnin and brucin may be separated from atropin by precipitating 
the former with platinic chloride. The precipitate should be washed 
with platinic chloride, and the strychnin and brucin subsequently recovered 
from the same. The atropin may be separated from the filtrate by adding 
ammonia, filtering, and shaking out with chloroform. The same prin- 
ciples may be employed in separating a mixture of the alkaloids of Nux 
Vomica, coca, and belladonna. 

Determination of Strychnin in Tablet Triturates. — Transfer a care- 
fully weighed amount, .3000 gram, of the powder to a 200-mil Squibb 
separator and moisten with 5 mils water. Add 1 mil stronger ammonia 



260 ALKALOIDAL DRUGS 

water. Agitate with 25 mils chloroform and allow to stand until separa- 
tion is complete. Draw off the chloroform into a second separator and 
repeat the agitation twice more with 25-mil portions of the solvent. After 
combining all of the fractions, wash the combined chloroformic solutions 
by agitation with 10 mils of distilled water and allow to stand fifteen 
minutes. Introduce a pledget of absorbent cotton into the stem of the 
separator and run off the chloroform into a tared dish, but do not allow 
the wash water to enter the orifice of the stop-cock. Add 10 mils chloro- 
form and when the water has entirely risen to the surface, run off the 
chloroform into the tared beaker. Wash off the outer surface of the stem 
of the separator with a little chloroform and then evaporate over a steam 
water-bath, using a fan or blower and removing from the bath as the last 
portions evaporate to avoid decrepitation. Dry at 100° to a constant 
weight and weigh as strychnin. The weight of strychnin may be checked 
by dissolving the residue in neutral alcohol, adding an excess of N/10 
sulphuric acid and titrating back with N/50 potassium hydroxide. 

Strychnin to Strychnin Sulphate 1.2815 according to U. S. P. 

One mil N/10 sulphuric acid is equivalent to 0.03342 gram of strych- 
nin and 0.04282 gram strychnin sulphate, crystalline (5H2O). 

In some cases, especially where the solvent dissolves substances from 
the tablet other than strychnin, it will be necessary to adopt the follow- 
ing modification of the above: 

The procedure is followed down to but not including the washing of 
the combined chloroform extract with water. Discard the alkaline solu- 
tion remaining in the first separator. Treat the combined chloroform 
extracts with 10 mils N/1 sulphuric acid and agitate. Allow to stand 
until separation is complete and collect the chloroform in a second sepa- 
rator. Repeat the extraction with N/1 sulphuric acid twice more, dis- 
card the chloroform and combine the acid fractions. Add stronger 
ammonia in excess, cool, and shake out with three successive portions of 
25 mils each of chloroform, finally combining all fractions. Wash the 
combined chloroform solutions by agitation with 10 mils of distilled water 
and allow to stand fifteen minutes. Draw off the solvent through a pled- 
get of absorbent cotton into a tared dish and finish the determination 
precisely as described. 

It has been the experience of the author that, in conducting assays 
of strychnin, reliance should be placed on a gravimetric estimation, and 
not on one obtained volumetrically. 

Determination of Strychnin in Liquid Products. — The method herein 
described is applicable to elixirs of iron and strychnin, quinin and other 
alkaloids being absent. 

Take a 50-mil volumetric flask, fill to mark with sample and weigh. 
Pour into an evaporating dish, washing out the flask with water and evap- 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 261 

orate off alcohol. Transfer to an 8-ounce Squibb separator. Add excess of 
ammonia. Agitate with 25 mils chloroform and allow to stand until sepa- 
ration is complete. Draw off the chloroform into a second separator 
and repeat the agitation twice more with 25-mil portions of the solvent. 
After combining all of the fractions, wash the combined chloroformic 
solutions by agitation with 10 mils of distilled water and allow to stand 
fifteen minutes. Introduce a pledget of absorbent cotton into the stem 
of the separator and run off the chloroform into a tared dish, but do not 
allow the wash water to enter the orifice of the stop-cock. Add 10 mils 
chloroform and when the water has entirely risen to the surface, run 
off the chloroform into the tared beaker. Wash off the outer surface of 
the stem of j the separator with a little chloroform and then evaporate over 
a steam water-bath, using a fan or blower and removing from the bath 
as the last portions evaporate to avoid decrepitation. Diy at 100° to 
a constant weight and weigh as strychnin. Calculations as above. 

Quantitative Estimation of Strychnin in Presence of Quinin (G. 
N. Watson 1 ). — Dissolve .05 to .1 gram of the mixed alkaloids (depend- 
ing on the amount of strychnin present) in 5 mils alcohol-hydrochloric 
acid mixture (9 parts alcohol 95 per cent and 1 part dilute hydrochloric 
acid), add 20 per cent solution of platinic chloride, drop by drop, while 
slightly agitating the mixture until the precipitation is complete. Add 
5 mils more of the solvent, cover with a watch-glass, set aside for one hour 
filter onto a Gooch, wash with alcohol, dry at 100° C. for fifteen minutes, 
cool and weigh. If the proportion of quinin is large, it will be necessary 
to add from 5 to 15 mils more of the solvent before filtering. It will also 
be necessary to decompose the precipitate with sodium hydroxide, dis- 
solve out the strychnin with chloroform, evaporate, dissolve the residue 
in the alcohol-hydrochloric acid mixture, and repeat the precipitation 
with platinic chloride. 

The chlorplatinate of strychnin contains 62 per cent of alkaloid. 

The quinin can be determined in the filtrate and washings by adding 
alkali, agitating with ether, separating, evaporating the ether, and weigh- 
ing the residue. 

To make this separation applicable to elixirs containing strychnin and 
quinin, a measured quantity of the sample should be made alkaline with 
ammonia and the alkaloids removed by means of Prolius mixture. After 
separating and evaporating the solvent the residue is subjected to the 
above procedure. 

Separation and Determination of Strychnin and Quinin (H. E. 
Buchbinder). — This procedure is applicable for determining small quanti- 
ties of strychnin in the presence of comparatively large quantities of quinin 

1 Journ. Amer. Pharm. Ass., 1915, 935. 



262 ALKALOIDAL DRUGS 

and can be used for assaying the elixirs of iron, quinin, and strychnin of 
the National Formulary. 

Take 50 mils of the sample, carefully measured and weighed. Transfer 
to a separator, dilute with water, and render ammoniacal. Shake out 
six times with ether-chloroform mixture (3-1). The extracts are com- 
bined, and the bulk of the solvent dispelled, the remainder being collected 
in a tared beaker and the container used for evaporation, carefully washed 
free from all alkaloid with the ether-chloroform mixture. Expel the sol- 
vent and dry at 100-105°. Cool and weigh as combined alkaloids. 

Dissolve the residue in 10 mils of alcohol, add 4 mils N/2 hydrochloric 
acid or sufficient to render the solution red to methyl red, with 1 mil N 
acid in excess for every 20 mils of the aqueous solution as finally made 
up (see below). (The volume of the solution is to be regulated by the 
amount of quinin present.) Add 36 mils water. (If there is more than 
six grams of total alkaloid add about seven mils of water for every addi- 
tional gram of quinin.) Add 3 mils saturated solution potassium oxalate. 
(Use 1 mil for every gram or less of quinin and 1 mil for every 20 mils of 
aqueous solution.) Stir and when precipitate has settled, place on steam- 
bath and heat to boiling temperature. Add a little alcohol to take up 
the undissolved precipitate at the boiling-point. Remove from bath, 
allow to cool spontaneously, breaking up surface film from time to time. 
Allow to stand at least five hours. Filter with vacuum, preserving fil- 
trate, and collect crystals on a plug of cotton inserted in the stem of an 
ordinary funnel. Wash six or seven times with cold water. Concen- 
trate filtrate and washings until all of the alcohol has been removed. Cool. 
Should there be a second crop of crystals, heat to redissolve, add J to 
1 mil N/1 hydrochloric acid and repeat above procedure. 

Adjust in a flask to a 5-7 per cent sulphuric acid solution at 50 mils, 
using water and dilute sulphuric acid. Add 4 mils potassium ferrocyan- 
ide solution 10 per cent, drop by drop, stirring constantly. Allow mix- 
ture to stand overnight. Filter and wash twice with 5-mil portions of 
5 per cent sulphuric acid containing a few drops of potassium ferrocyanide. 
(Do not attempt to remove all of the precipitate from the flask.) Trans- 
fer precipitate on filter to 1 a small separator using a fine jet of water. To 
the flask add 5 mils strong ammonia and 15 mils chloroform. Agitate 
and pour into separator. Rinse and agitate flask twice more with 10- 
mil portions of chloroform, pouring each into separator. Agitate the sepa- 
rator, collect chloroform in another separator and repeat the extraction 
twice more. Combine all of the chloroform extracts, wash with water, 
filter into a tared beaker through a plug of absorbent cotton in the stem 
of the separator, wash out separator and cotton with a portion of chloro- 
form, evaporate solvent, dry at 100-105° and weigh. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 263 

ALKALOIDS OF PEGANUM HARMALA 

Harmin, C13H12N2O. 

Harmalin, C13H14N2O. 

Harmalol, Ci 2 Hi 2 N 2 0. 
These alkaloids occur in the seeds of Peganum harmala (Zygophyl- 
lacese), an herbaceous plant growing in Southern Europe and parts of 
Asia. The seeds are called Harmal or Ispanol and in India are used as 
a genito-urinary stimulant, anthelmintic, and emmenagogue. They are 
also narcotic and are used for the same purposes as Cannabis sativa. These 
alkaloids or preparations containing the drug are not used to any great 
extent. 

Extract of P. harmala is used as a red dye. 

Harmin 

Harmin crystallizes from alcohol in needles, melting 256-257°, inactive, 
subliming unchanged and sparingly soluble in water, alcohol, and ether. 
Its salts are colorless and show an indigo-blue fluorescence in aqueous 
solution. It dissolves in concentrated sulphuric acid to a greenish fluores- 
cent solution. 

Harmin contains an OCH3 group which may be eliminated by HC1 
or HI, yielding harmol, a phenol. The latter crystallizes in needles melt- 
ing 321°, 

Harmalin 

This alkaloid crystallizes from methyl alcohol in plates or needles, 
melting with decomposition 238°. It is optically inactive, almost insolu- 
ble in water, sparingly soluble in alcohol and ether, and may be precipi- 
tated from an alcoholic solution by ether. Its salts are yellow and in 
aqueous solution,. show a blue fluorescence, but the solution in concen- 
trated sulphuric acid does not fluoresce. 

When dissolved in cold pyridin and treated with acetyl chloride, har- 
malin forms an acetyl derivative which crystallizes from alcohol in needles 
melting 204-205° C. 

Harmalin contains an OCH3 group which is eliminated by HC1, yield- 
ing harmalol, a phenolic alkaloid, which crystallizes in red needles, melt- 
ing 212°. It is probable that the latter substance exists to a certain extent 
in the plant. Harmalol dissolves in water with considerable difficulty, 
yielding a yellowish solution with fluorescence. Acids or alkalies destroy 
the fluorescence, 



264 ALKALOIDAL DRUGS, 

ALKALOIDS OF THE ACONITE GROUP 

Aconitin, C34H47NO11. 
f Japaconitin, C34H49NO11. 

Indaconitin, C34H47NO10. 

Pseudaconitin, C36H51NO12. 

Bikhaconitin, C36H51NO11. 

Jesaconitin, C40H51NO12. 

Lycaconitin, C27H34N2O6 • 2H2O. 

Myoctonin. 
^-~ Lapaconitin, C34H48N2O8. 

Septentrionalin, C31H48N2O9. 
: Cynoctonin, C36H54N2O13. 
^Atisin, C22H31NO2. 

Palmatisin. 

Most of the different species of Aconitum (family Ranunculacese) con- 
tain one or more characteristic alkaloids, some extremely poisonous, and 
others with feeble toxic properties, and from a close study of some of the 
more commonly known of these plants, it appears that each is characterized 
by a distinct alkaloid. The alkaloids occur in all parts of the plants and 
in some pharmacopoeias both the leaves and the root are official, though 
in ours, only the root is recognized. The plant designated in the U. S. 
Pharmacopoeia is A. napellus. The root is about 2-4 inches long and 
f to 1 inch in diameter at the widest portion, being tuberous and of irregu- 
lar conical form, brownish externally, white or light brown and starchy 
within. It is biennial and normally paired, one tuber of each pair when 
mature bearing a flowering stem, the other having a bud. The parent 
tubers may be distinguished by the scar of the stem, and the spongy or 
hollow condition of the root. The fresh leaves have a faint narcotic odor, 
and a bitterish herbaceous taste, afterwards acrid with a feeling of numb- 
ness and tingling on the inside of the lips, tongue, and* fauces which may 
last an hour or more. The dried leaves produce the same sensation. 
The root has a sweetish taste at first, but afterwards the same effect as 
the leaves. 

Of late years much "Japanese Aconite " has been coming into the 
markets of the United States. The species yielding this drug is A. fisheri. 
The drug usually consists of mother (with stem bases) and daughter tubers 
(with buds), which may be distinguished from those of the official aconite 
by their much smaller size and weight, less wrinkled, and not twisted 
appearance, more or less short conical shape, generally more mealy con- 
dition due to starch, and microscopically by the different arrangement 
of the fibro-vascular bundles, which is usually not so markedly star shaped. 



ALKALOIDS WHICH PROBABLY CONTAIN A PRYIDIN NUCLEUS 265 

Adulteration of aconite with Imperatoria ostruthium, masterwort, 
is reported. 

Commercial aconitin may consist of a mixture of one or more alkaloids, 
depending on the drug from which the extraction was made. The whole 
question of aconite analysis has been the subject of considerable contro- 
versy, but Dunston and his collaborators have done a great service in 
sifting out the data and showing the source of the various aconitins. 

A. napellus contains aconitin. 

A. fischeri contains japaconitin. 

A. chasmanthum contains indaconitin. 

A. dinorrhizum contains pseudaconiton. 

A. spicatum contains bikhaconitin. 

A. japonic um contains jesaconitin. 

A. vulparia or A. lycoctonum contains lycaconitin and myoctonin. 

A. lycoconum or A. septentrionale contains lapaconitin and sep- 

tentrionalin. 
A. hetrophyllum contains atisin. 
A. palmatum contains palmatisin. 

In addition to these there are a number of aconites which contain bases 
as yet little studied. 

Aconitic acid is apparently a constant constituent of aconite and it 
is probable that the alkaloids are in part combined in the plant. 

The interest of the drug analyst will be chiefly confined to the chem- 
istry of A. napellus, though, as indicated above, the commercial alkaloids 
may consist of one or many individuals of the aconite group. These 
alkaloids are extremely poisonous, their employment as remedial agents 
is limited, and they will be encountered only rarely in the general run of 
drug work. 

Aconite is a cardiac and nervous sedative, and is used in fevers as a 
diaphoretic, in cardiac hypertrophy, colds, neuralgia, rheumatism, and 
gout. Its antidote is Digitalis. 

The alkaloid aconitin is dispensed in the form of pills and tablets, 
usually of small grainage, t^q down to 10 \ or less, and it is also used 
in ointments. Extracts of both root and leaves occur as such, and in 
pills alone. Neuralgic pills contain aconite combined with other strong 
drugs, including morphin, strychnin, arsenous acid, and quinin; one of 
the old-fashioned so-called " shot-gun " prescriptions contains aconite 
with Hyoscyamus, ignatia, opium, belladonna, Conium, stramonium, and 
Cannabis; fever mixtures contain aconite with morphin, tartar emetic, 
and ipecac; also with Bryonia and belladonna; cold mixtures consist of 
aconite, quinin, Capsicum, ipecac, and opium; aconite, quinin, ammonium 
chloride, camphor, opium, and belladonna; aconite, sanguinarin, mor- 



266 



ALKALOIDAL DRUGS 



phin, atropin, ipecac, tar, and tartar emetic for coughs; aconite, bella- 
donna, aloin, calomel, and quinin; aconite, camphor, opium, and potas- 
sium nitrate; aconite, morphin, atropin, and calomel; aconite, Bryonia, 
belladonna, and mercuric iodide for tonsillitis; aconite, Cimicifuga, bella- 
donna, and Colchicum for sciatica; aconite, quinin, opium, ipecac, and 
acetphenidin. Aconite is seldom dispensed in liquid preparations owing 
to the ease with which its active constituent is decomposed. In fact, 
when the drug is dispensed in pills and tablets it is never safe to depend 
on its potency unless chemically or physiologically tested, because the 
manipulation of pill-making is often rigorous enough to break down the 
highly sensitive aconitin. 

The chemical structure of the aconitins is still a subject of research, 
but it is known that they are all derivatives of bases, probably closely 
related, known as " aconins." 

Dr. Carr * in the new edition of Allen has summarized the situation 
as follows: 



Name 


Composition 


Formula 






OAc 


Aconitin 


Acetylbenzoylaconin 


C2iH 27 3 N— (OMe) 4 




OBz 






OAc 


Japaconitin 


Acetylbenzoyljapoconin 


C 2 iH 29 3 N— (OMe) 4 






OBz 






OAc 


Indaconitin 


Acetylbenzoylpseudaconin 


C21H27O2N— (OMe) 4 






OBz 






OAc 


Pseudaconitin 


Acetylveratrylpseudaconin 


C 21 H 2 70 2 N— (OMe) 4 

OCOC 6 H 3 (OMe) 2 
OAc 


Bikhaconitin 


Acetylveratrylbikhaconin 


C 2 iH 27 ON— (OMe) 4 






OCOC 6 H 3 (OMe) 2 






OCOC 6 H 4 (OMe) 


Jesaconitin 


B enzoylanisy laconin 


C21H27ON— (OMe) 4 






OBz 



The bases undergo hydrolysis with ease, yielding the acid components 
and the parent base. The hydrolysis occurs in stages and in the drug 
itself there will be found not only the specific aconitin, but its various 
degradation products. It is due to this latter fact that a chemical assay 
of an aconite preparation or drug has little value as an indication of the 
1 Commercial Organic Analysis, Allen, Vol. 7, page 257. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 267 

therapeutic efficiency. The degradation products are much less active 
than the alkaloids themselves. 

All of the above aconitins are extremely poisonous and if they are 
suspected, caution should always be observed in testing products physio- 
logically. 

Aconitin 

This alkaloid is the only crystalline base of A. napellus, but is seldom 
encountered in a state of chemical purity, being accompanied with the other 
aconin derivatives of the drug. It may be purified by recrystallizing one 
of its salts, separating the base, and crystallizing it from alcohol or a mix- 
ture of alcohol and ether. It is readily soluble in chloroform and benzol, 
somewhat less so in alcohol and ether, slightly soluble in hot water, and 
only sparingly in cold water and petroleum ether. It is dextrorotatory 
in alcohol and its salts are lsevorotatory. The purified base melts 197- 
198°, but if heated slowly it begins to decompose at 182°, and it will give 
figures anywhere from this temperature up to 200°. It possesses (a) D 
= +110 in 3 per cent alcohol. 

Aconitin produces a tingling and numbing sensation of the tongue, 
which spreads to the lips and roof of the mouth and may last for hours. 
Extremely dilute solutions will produce this sensation and it is one of the 
best tests, though it must be performed with great caution and only in 
dilute solutions. To make the test the alkaloid should be dissolved in 
a little dilute acetic acid and the solution adjusted to 1-1000; then an 
aliquot of this solution may be diluted to 1-100000 with water and 25 mils 
taken into the mouth, rinsed well for half a minute between the tongue 
and cheeks after the manner of a mouth wash and then expelled. If at 
the expiration of ten to fifteen minutes no tingling sensation has appeared 
a slightly stronger solution, 1-90000, may be used and so on until the 
sensation is obtained. If the substance under examination is pure aconi- 
tin, the effect will be readily apparent at the dilution of 1-100000, and 
the author has tested samples which are potent in a dilution of over a 
million parts of water. 

On treating aconitin with nitric acid, evaporating and adding a few 
drops of alcoholic potash, the characteristic odor of ethyl benzoate is 
given off. No purple color is obtained on adding the alcoholic potash, 
but pseudoaconitin is stated to yield a purplish tint. 

A solution of great dilution when applied to the eye or upper eyelid 
causes contraction of the pupil, with a sense of heat and tingling. 

Aconitin gives no color reactions on which any reliance can be placed. 
It is precipitated by the general alkaloidal reagents and some of the insolu- 
ble salts form crystals having sharp melting-points and characteristic 
microscopic forms. The aurochloride is very insoluble and is precipitated 



268 ALKALOIDAL DRUGS 






on adding gold chloride to a solution of aconitin in hydrochloric acid in 
presence of sodium chloride. This salt when washed and dried in vacuo, 
may be obtained in three modifications — from alcohol, aqueous alcohol, 
chloroform and ether, melting 135°, from absolute alcohol, melting 152°, 
and on recrystallizing the latter from a mixture of chloroform and ether, 
melting 176°. The precipitate obtained with potassium permanganate is 
crystalline and may be obtained from dilutions of 1-500; its crystalline form 
should be compared under the microscope with the crystals obtained with 
cocain. Hydrastin and papaverin in concentrated solution are said to 
give crystalline precipitates with permanganate. 

The periodide is very insoluble. Sparingly soluble precipitates are 
obtained with potassium iodide and ammonium sulphocyanide. Platinic 
chloride does not give a precipitate unless the solution is very concen- 
trated, mercuric chloride, potassium chromate, ferrocyanide, and ferricy- 
anide give precipitates only in fairly concentrated solutions. 

Aconitin is a strong base and forms well-defined salts with mineral 
acids. It is seldom used in the form of a salt, however, nearly always 
appearing in medicines as the straight alkaloid. It gives di- and tri- 
acetyl derivatives with acetyl chloride, but no derivatives with acetic 
anhydride. 

The hydrolysis of aconitin takes place in two stages, first to acetic 
acid and benzaconin (picraconitin, napellin, or benzoyl aconin), 

C34H47NO11+H2O = C32H45NO10+CH3COOH, 

and then benzaconin is further hydrolyzed to benzoic acid and aconin 
(C 3 2H45NOio+H20 = C25H4iN07+C6H5COOH). The latter is an amor- 
phous, hygroscopic alkaloid, soluble in water, chloroform, alcohol and 
sparingly in ether. Benzaconin is also present in the aconite root, and 
is readily soluble in alcohol, ether, and chloroform. It does not produce 
the characteristic tingling of aconitin and is much less toxic. 

Neutral solutions of aconin are lsevorotatory, the acid solution is dextro. 

It reduces Fehling's solution and ammoniacal silver nitrate. 

Japaconitin 

This alkaloid is obtained from a species of aconite indigenous in Japan, 
and formerly thought to be A. fisheri, but now considered a distinct 
species. Japaconitin melts 204-205° and resembles aconitin closely. 
Its rotation differs somewhat and its hydriodide melts 208-210°, while 
aconitin hydriodide melts 226°. Its aurochlorides melt 153° (spontane- 
ous evaporation from chloroform) and 231° (separation from alcohol). In 
its chemical tests it cannot be distinguished from aconitin. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 269 

Indaconitin 

Indaconitin occurs in A. chasmanthum, a native plant of India. It 
melts at 202-203° and its rotatory power and that of its salts are some- 
what less than those of aconitin. It hydrolyzes in two stages, first to 
acetic acid and indbenzaconin, and then to benzoic acid and pseudaconin. 
Its chemical and physical behavior is similar to that of aconitin. 

Pseudaconitin 

Pseudaconitin differs from the previous bases in containing the vera- 
tryl group instead of the benzoyl, and yields veratric acid on hydrolysis 
with alcoholic potash. Its physiological action is more intense than the 
other aconite alkaloids. It melts 211-212°. The base is dextro- and 
its salts laevorotatory. The aurochloride forms yellow needles, melting 
236-238°. The nitrate with 3 molecules of water is difficultly soluble 
and melts 185-186°. It gives a purple-red color when subjected to Vitali's 
test and a similar color when warmed with concentrated sulphuric acid. 

Veratric acid is soluble in alcohol and ether and only slightly soluble 
in water, and may be removed from an acidulated solution. It crystal- 
lizes in prisms containing one molecule of water and melts 178-180°. It 
is the dimethyl ether of protocatechuic acid. 

COOH 
^NoCHg 

\/ 
OCHs 

Pseudaconin, the basic product of hydrolysis, crystallizes from alcohol, 
melting 94-95°. 

Bikhaconitin 

This alkaloid like the former contains a veratryl group in its mole- 
cule and yields veratric acid on hydrolysis. It crystallizes from ether 
in white button-shaped masses composed of concentric rings, differing 
from its related bases in this respect. It melts 118-123°. 

Jesaconitin 

This is an amorphous alkaloid from A. japonicum and contains no 
acetyl group. On hydrolysis it yields anisic and benzoic acids and aconin. 
Anisic acid is paramethoxybenzoic acid, readily soluble in ether, alcohol, 
and hot water, melting 184° C. 

Lycaconitin 
Lycaconitin and myoctonin are amorphous bases of A. vulparia. The 
former is soluble in ordinary organic solvents with the exception of petro- 



270 ALKALOIDAL DRUGS 

leum ether, and only sparingly in water. It is precipitated by Mayers 
reagent, tannin, bromine water, and iodine, but not by platinic chloride, 
mercuric chloride, potassium iodide, nor phosphomolybdic acid. Its basic 
product of hydrolysis is lycaconin, melting 90-92°, soluble in alcohol, 
chloroform, ether, and benzol and giving a fluorescent solution in water. 

Myoctonin 

This base is but slightly soluble in ether, but in other respects closely 
resembles lycaconitin. It yields lycaconin on hydrolysis. It has a bitter 
taste but does not produce a tingling sensation. It is a strong poison, 
however, and is reported to resemble curare in its action. 

Lapaconitin, Septentrionalin and Cynoctonin 

These three alkaloids occur in A. lycoctonum, or according to some 
authorities in A. septentrionale. Lapaconitin melts 205°, septentrion- 
alin 129°, and cynoctonin 137°. The first mentioned gives fluorescent 
solutions but the others do not. Lapaconitin is bitter and a heart depres- 
sant, the others are local anesthetics. 

Atisin 

This alkaloid occurs in A. heterophyllum and is not toxic. The drug 
is employed as a bitter tonic. Atisin forms a colorless varnish melting 
85°, readily soluble in water and organic solvents except petroleum ether. 
It is lsevorotatory and its salts dextro. With sulphuric acid it gives a 
yellow color gradually becoming red. It is not hydrolyzed by acids or 
alkalies but apparently forms a new base. 

Palmatisin 

Palmatisin occurs in A. palmatum and forms crystals from ether, 
melting 285°. It resembles atisin in its physiological properties. 

Aconitic Acid 

CH 2 — COOH 

I 

C— COOH 

II 

CH— COOH 

Aconitic acid, which appears to be a constant constituent of aconite 
root, is closely related to citric acid in composition. It forms colorless 
crystals, melting 186° C. (191° Mullikin), soluble in water, alcohol, and 
ether. Its aqueous solution gives no precipitate when boiled with excess 
of calcium hydroxide. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 271 



M. Pt. and (a) D 

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272 ALKALOIDAL DRUGS 

The problems which may confront the drug analyst in connection with 
the aconite alkaloids are as follows: the identification of "aconitin," 
the determination of the amount present in a mixture, the determination 
as to whether the amount of alkaloid originally present agrees with that 
claimed on the label (taking into account the ease with which aconitin 
decomposes), the question as to the identity of the drug used in compound- 
ing an extract of aconite and the actual identity of an aconitin. The word 
aconitin above is written in quotations in order to emphasize the fact 
that the identity of an aconitin does not necessarily require one to report 
the exact individual in question. The first three propositions are those 
requiring the chief consideration of the analyst, the others may occur in 
rare cases. Special attention must be called to the third proposition above 
mentioned; it often happens that a manufacturer acts in perfect good 
faith and makes up his formula in the proper proportions, but in the course 
of time, and due to the various hands through which a product must pass 
to the final consumer and the conditions under which it is kept, its potency 
becomes impaired and the blame is unjustly carried back to the original 
source. 

In the general scheme of medicinal analysis aconitin will appear when 
the solution has been made alkaline and shaken out with petroleum ether 
and with ether. These two fractions will carry a large proportion of the 
aconitin, the latter the greater proportion unless the quantity is extremely 
small. The first suggestion of aconitin will occur when a residue evapo- 
rated with nitric acid, is treated with alcoholic potash and the character- 
istic odor of ethyl benzoate is obtained. Cocain will give the same reac- 
tion, but if this is followed by a physiological test, conducted by rubbing 
a minute quantity of the residue on the tongue and lips, cocain produces 
numbness while aconitin will give the characteristic tingling. Follow- 
ing this a portion of the residue should be dissolved in a small quantity 
of dilute acid and portions of this solution treated with gold chloride and 
potassium permanganate, the characteristic forms of the crystals observed 
under the microscope in comparison with those produced with a known 
sample of aconitin, and the melting-point of the auxochloride determined. 
If there is sufficient quantity of the residue and it is not contaminated 
with other alkaloids it should be crystallized, dried in vacuo, and its melt- 
ing-point determined. When this test is applied the sulphuric acid should 
be heated to 160-170° before introducing the capillary tube containing 
the alkaloid, and the acid rapidly heated until the crystals melt. 

Unless the analyst is familiar with aconitin he should use great caution 
in performing the physiological test, and for safety the procedure recom- 
mended on page 267 ought to be observed. 

In order to determine the amount of aconitin in a fluid, solid extract, 
or tincture, the procedure recommended in the chapter on Drug Assays 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 273 

can be used to advantage. The residue will be contaminated to a greater 
or less extent with other bases, and it may be desirable to dissolve the resi- 
due in dilute acetic acid, make up to a definite volume, and then use 
aliquots of this in a Squibb test, comparing the activity with that obtained 
with a sample of aconitin of known purity prepared by the worker him- 
self. By this means the quantity of pure aconitin in the original product 
can be calculated. From mixtures with other non-alkaloid-bearing drugs, 
aconitin may be separated by extraction from an ammoniacal solution 
with ether, purified by redissolving in acid, separating any acid or neutral 
principles by the usual solvents and then removing the aconitin with ether 
from alkaline solution. The therapeutic activity of a mixture, with respect 
to the aconitin present, can be obtained by performing a Squibb test on 
a solution of the original substance precisely as described by Taylor's 
method on page 27. This procedure is about the only one known for 
estimating aconitin in mixtures with the other alkaloids with which it is dis- 
pensed. No methods have been evolved for separating aconitin chemic- 
ally from other bases, and any which might be based on its products of 
hydrolysis are too uncertain to be considered. Of course the base may 
be easily separated from morphin by shaking it aut with ether from a solu- 
tion made slightly alkaline with caustic alkali. The fact that it is resist- 
ant to permanganate, while quinin, strychnin, and many other bases 
reduce this reagent, is a point which may be used to advantage in solving 
this problem and offers an attractive field for investigation. 

If the amount of aconitin found on analysis does not agree with that 
claimed, it must not be concluded that the proper quantity was not 
originally absent. The quantity of acid products of hydrolysis present 
as well as other basic substances must be determined and the sum total, 
properly interpreted, used as evidence to substantiate or refute the claim 
on the label. 

The identification of the species of aconitin used in the preparation 
of a medicine requires careful work. Standard preparations specify the 
use of A. napellus, and as physicians regulate their dosage on the assump- 
tion that the standard drug with which they are familiar, has been 
employed, and as it appears that the several " aconitins " vary in thera- 
peutic efficiency and possibly physiological activity, any variation in the 
specific drug employed may lead to disastrous results. Hence the drug 
analyst may be called upon to settle the question as to whether the drug 
in hand is A. napellus or some other species. The alkaloid must be sepa- 
rated and carefully purified, and after determining its melting-point and 
that of its aurochloride, it must be hydrolyzed and both the acid and 
basic products of hydrolysis identified beyond question. When this is 
done by referring to the table on page 271 the " aconitin " in hand will 
be apparent, and when this is determined the drug employed is known. 



274 ALKALOIDAL DRUGS 

BASES OF CEVADILLA AND VERATRUM 

Cevadilla or Sabadilla seed and Veratrum root possess certain similar 
physiological properties, especially in relation to their action on the heart, 
and while there may be no similarity in the chemical composition of the 
bases, and neither drug possesses an alkaloid in common, unless it be 
veratridin or cevadin, it is advisable, to avoid confusion, to consider the 
drugs together. The term " veratrin " has been used for a long time in 
alkaloidal chemistry and has become so firmly established that, in the 
minds of many, it is attributed to an individual alkaloid. This is further 
complicated by the fact that the U. S. and other Pharmacopoeias recog- 
nize the term, with the amplification that it is "an alkaloid or .mixture 
of alkaloids," and then proceed to describe its properties, even to defining 
a specific melting-point. As a matter of fact the so-called " veratrin " 
is realty a mixture of the bases obtained from the seeds of Cevadilla, 
the proportions of which must necessarily vary from time to time. The 
chief component of " veratrin " is cevadin, an alkaloid which has not 
been found in the rhizome of Veratrum viride or V. album, and which 
is apparently different in composition from any of the bases occurring in 
the latter. Hence we see that the term " veratrin," which will prob- 
ably always persist, does not apply to alkaloids from the genus Veratrum, 
and account of this anomaly it is expedient to conjointly discuss the bases 
of these drugs. 

In this introduction attention must be called to an examination of 
the bases from Zygadenus intermedius conducted by Heyl 1 and his associ- 
ates, who extracted from the leaves of this plant, called locally Death 
Camas, a new base to which the name zygadenin has been given and which, 
in its chemical properties, resembles cevadin. It differs from the latter, 
however, in its ultimate composition, which is given as C39H63NO10, and 
in having (ci) D — 48.2°, while cevadin is inactive. 

Prof. Kraemer states that the bulbs of Z. venenosum contain veratral- 
bin, sabadin and sabadinin. 

CEVADILLA BASES 

Cevadin, C32H49NO9. 
Veratridin, Cs^sNOs. (?) 
Sabadin, C29H51NO8. (?) 
Sabadinin, C27H45NO8. (?) 
Sabadillin (Cevadillin) C^HssNOs. (?) 

The plant Schoenocaulon officinale (Lilacese), growing in Mexico and 
the West Indies, furnishes the seeds from which these bases are obtained, 
1 J. Am. Chem. Soc, 1911, 206; 1913, 258. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 275 

and the alkaloidal content varies from 1 to 3 per cent, with cevadin pre- 
dominating. Tiglic and veratric acid also exist in the drug, either in the 
free state or in combination. The seeds are not recognized in the U. S. 
Pharmacopoeia, but they find a place in the Swiss standard, and a method 
of assay is included therewith. American manufacturers apparently make 
little use of the drug and from all reports the seeds are used chiefly for 
preparing " veratrin." The ground seed is used as an ingredient for 
destroying vermin in the hair. The alkaloidal mixture " veratrin " is 
a drastic and irritant cathartic and has been employed in articular rheu- 
matism, ascites, as a cardiac sedative, and externally in superficial neural- 
gias, sciatica, and some forms of pruritus. It is a dangerous drug for indis- 
criminate use and will be rarely found in unknown mixtures. 

Cevadin 

Cevadin crystallizes from alcohol with 2 molecules of the solvent, 
which is removed with difficulty when heated to 100° C, but is readily 
removed with boiling water, and the anhydrous base melts 205-206°. 
It dissolves in all of the organic solvents except petroleum ether, and its 
solutions are inactive to polarized light. It is extremely poisonous and 
has the peculiar property of producing violent sneezing. It gives crystal- 
line salts with gold chloride, picric acid and mercuric chloride, and an 
amorphous precipitate with platinic chloride. It yields precipitates with 
the usual alkaloidal precipitants. 

The individual color reactions of this base have not been reported. 
All of the tests described in the literature refer to the mixed bases, and 
these reactions will be described subsequently. 

Cevadin is readily hydrolyzed by aqueous and alcoholic alkaline solu- 
tions. It is first transformed to angelic acid and a new base called 
cevin. Then angelic acid changes to the isomeric cevadic or tiglic acid, 
which is partly broken up into acetic and propionic acids, and the cevin 
forms non-basic resinous products. The products of hydrolysis may be 
obtained by boiling the base with alcoholic potash under a reflux con- 
denser, diluting, acidifying, and shaking out the acid products with ether, 
and then making alkaline and removing cevin by amy] alcohol. The 
ether solution of the acids is evaporated and the residue distilled, and as 
the fraction coming over at 180-190° is collected and cooled, it will 
yield crystals of tiglic acid, melting 64-65°. Tiglic acid is methyl 
crotonic acid, 

CH 3 CH=C(CH3)COOH. 

Cevin obtained on evaporating the amyl alcohol, melts 145° and dis- 
solves in alcohol and acids, but only sparingly in chloroform, and scarcely 




ALKALOIDAL DRUGS 

in ether. It is precipitated by caustic alkalies, but not by carbonates, 
and reduces Fehling's solution and ammoniacal silver nitrate. 

Veratridin 

This is an amorphous base, and its properties are not well known 
owing to the difficulty of obtaining it pure. It melts at 150° or 180° 
and forms a fairly insoluble nitrate and sulphate. On hydrolysis it yields 
veratric or dimethyl protocatechuic acid and a basic product, verin or 
veratroidin, which bears a close resemblance to cevin obtained from ceva- 
din. Veratric acid is one of the products of hydrolysis of pseudaconitin 
and has already beeen described. 

Sabadin 

Sabadin is a crystalline base, melting 238-240°. It is precipitated 
from its solutions by warming with sodium carbonate, and shaking with 
ether. On subsequent crystallization from alcohol it is only sparingly 
dissolved in ether. It is claimed to give no color with nitric acid, but 
dissolves in sulphuric acid with a yellow color and green fluorescence, 
which soon disappears, and a blood-red to violet shade develops. 

Sabadinin 

This base is separated in a similar manner to sabadin which it resembles 
in some of its properties and color tests thus far studied. It melts 160° 
and does not produce sneezing. 

Sabadillin 

Sabadillin has been reported as occurring in commercial veratrin. It 
yields tiglic acid on hydrolysis. 

The above descriptions of the bases show that, with the possible 
exception of cevadin, the chemistry of this group is still in its pioneer state. 
From an analytical standpoint we can only consider the alkaloids en masse, 
because as yet we know little or nothing of the solubilities of the sub- 
sidiary bases, and there is no scheme for separating them when they occur 
in the quantity usually available. 

There are several color tests attributed to the purified residue. Sul- 
phuric acid dissolves the bases to a yellow solution with a greenish fluores- 
cence, changing to blood-red and finally to purple. Hydrochloric acid 
gives a permanent blood-red, and nitric acid a yellow solution, often pink- 
ish at moment of solution. Sulphuric acid containing furfurol gives a 
dark-green color becoming violet on warming. 



■^ 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 277 

These tests, taken in conjunction with the physiological action of the 
alkaloids (intense sneezing), and the production of the characteristic acids 
on hydrolysis, furnish the necessary evidence for deciding as to the identity 
of the bases and the drug from which they are obtained. None of the 
cevadilla bases give reactions which might confuse them with the opium, 
Nux Vomica, coca, belladonna, and cinchona bases, for all of which there 
are certain well-defined tests. 

There is, however, some likelihood of mistaking a mixed residue from 
Veratrum viride or V. album for one from Cevadilla, as the former con- 
tains veratralbin, which resembles cevadin in its properties and gives rise 
to a series of color reactions similar to those above described. 

With the exception of veratralbin, most of the Veratrum bases when 
isolated are but sparingly soluble in ether. However, this property can- 
not be depended upon for making a separation from alkaline solutions 
with immiscible solvents, as jervin and probably the other bases are 
fairly soluble in ether when freshly precipitated. Protoveratrin and pro- 
toveratridin are but sparingly soluble in ether or chloroform, and portions 
may still be found in the alkaline solution after shaking out with these 
solvents. The solubility of the cevadilla bases is such that they are prac- 
tically all removed by ether from alkaline solution. 

THE VERATRUM ALKALOIDS 

Jervin, C26H37NO3. 
Rubijervin, C26H43NO2. 
Pseudojervin, C29H43NO7. 
Protoveratrin, C32H51NO11. 
Protoveratridin, C26H45NO8. 
Veratralbin, C^sH^NOs or C32H03NO9. 

The roots of Veratrum album from Southern Europe and of V. viride, 
Bunch flower family (Melanthiacese) , from the United States and prob- 
ably other related species contain these alkaloids. Wright reports ceva- 
din in the roots of V. viride and possibly veratridin. The two species 
mentioned are official in the U. S. Pharmacopoeia. V. viride, called the 
American hellebore, is a native perennial herb, 2 to 7 feet high growing 
in swamps, wet woods and meadows, closely associated with skunk cab- 
bage. It produces large bright-green leaves and is a very conspicuous 
plant in the meadows and swamps. 

Veratrum is employed medicinally in the form of its extract, but its 
use is limited and is attended with so much danger that it will seldom be 
encountered in practice. It is present in small dosage in liver pills mixed 
with jalap, aloes, gamboge, leptandra, Podophyllum resin, Capsicum, 



278 ALKALOIDAL DRUGS 

croton oil, and calomel. It is a heart depressant and is used in certain 
aortic conditions. 

The percentage of total bases in V. viride seems to vary considerably 
running from .2 to over 1 per cent. In V. album, Wright found over 4 
per cent of alkaloids with veratralbin predominating, though he reported 
but a trace in V. viride, cevadin, and jervin being the chief bases in the 
latter. 



Jervin 

Jervin crystallizes in white acicular prisms containing 2H2O, and on 
drying at 100° it melts 241°. It is readily soluble in chloroform, less so 
in alcohol and ether, and almost insoluble in benzol and petroleum ether. 
It is not hydrolyzed by boiling alcoholic potash. It is a strong base 
and forms well-defined salts, the acetate and phosphate being easily dis- 
solved in water, but the hydrochloride, nitrate, and sulphate are only 
sparingly soluble especially in the presence of the free acid. The less 
soluble salts may be^ prepared by treating a solution of the phosphate or 
acetate with the alkali salt of the acid. 

Jervin gives a yellow color with sulphuric acid, changing to brownish, 
greenish brown, and on longer standing to green, which finally disappears. 
Pseudojervin also gives the green shade, but the other Veratrum bases 
ultimately produce a reddish tint. Sulphuric acid and sugar produce a 
violet color, changing to blue. This reaction is not very satisfactory, 
however, as the mixture first becomes dark brown and after a time a vio- 
let tint appears along the edges and in thin layers, and then gradually 
turns blue. Froehde's reagent acts in the same manner as sulphuric acid 
alone. Nitric acid gives a pinkish tint, the solution soon turning orange 
and then slowly fades. Hydrochloric acid gives a light yellow color. 

Precipitates are obtained with the common alkaloidal reagents includ- 
ing tannic acid. 

Rubijervin 

Rubijervin crystallizes in acicular prisms containing one molecule of 
water, and on drying melts 234°. It is somewhat soluble in alcohol, 
hot chloroform, and benzol, and slightly soluble in ether and petroleum 
ether. Its salts are much more soluble than those of jervin. It gives a 
yellow solution with sulphuric acid, turning brownish, reddish brown, and 
finally purplish. If the brownish-red liquid is diluted with water, the 
color changes to crimson and passes through several violet and purple 
shades to deep blue. It is precipitated by the common alkaloidal precipi- 
tants with the exception of tannic acid and platinic chloride. 



ALKALOIDS WHICH PROBABLY CONTAIN A PYRIDIN NUCLEUS 279 

Pseudojervin 

Pseudojervin crystallizes in hexagonal plates, melting 304°. It is 
readily soluble in chloroform, slightly soluble in alcohol and benzol, and 
practically insoluble in ether and petroleum ether. The sulphate is 
slightly soluble in cold but readily in hot water, and the hydrochloride 
is only sparingly soluble in water either hot or cold, but is dissolved in water 
containing a little free acid. 

With sulphuric acid it gives the same color tests as jervin, and is 
precipitated by the same reagents except platinic chloride. 

Veratralbin 

This alkaloid is amorphous and melts at 149°. Its salts are amor- 
phous. It dissolves easily in the ordinary organic solvents. Its color 
reactions are similar to those obtained with cevadin; sulphuric acid pro- 
duces a yellow color, changing to orange and blood-red with a greenish 
fluorescence; nitric acid a fleeting rose tint, the solution becoming pale 
yellow; dilute hydrochloric acid a rose color. It is precipitated by the 
common alkaloidal reagents. 

Protoveratrin 

This alkaloid, which seems to be the most active of the group, crystal- 
lizes in microscopic plates, melting 245-250°. It is sparingly soluble in 
the organic solvents. It gives a green color with sulphuric acid which 
passes through blue to violet. Hydrochloric and phosphoric acids give 
a dark cherry red and a butyric odor.- It is not precipitated by tannic 
acid, platinic chloride, or mercuric chloride, but is thrown down by the 
other common reagents. 

It is stated that protoveratrin may be separated from the other bases 
by treating an acetic acid solution with solid glacial phosphoric acid, fil- 
tering, and extracting the protoveratrin with ether after rendering am- 
moniacal. 

Protoveratridin 

This base crystallizes in plates melting at 265°. It is insoluble in 
ether, benzol, and petroleum ether and only to a slight extent in alcohol 
and chloroform. With sulphuric acid it gives a violet to cherry-red color 
and with hydrochloric acid a bright red color and a butyric odor. It is 
not precipitated by platinic chloride or potassium cadmium iodide. 

An alkaloidal residue consisting of the Veratrum bases will give indi- 
cations of its identity by evolving a butyric odor when treated with acids 
at the same time its color reactions are determined. The mixed bases 



280 ALKALOIDAL DRUGS 

will give negative tests with the reagents employed for the other well- 
known alkaloids. 

Farr and Wright have evolved a method for separating jervin from 
its accompanying bases. The alkaloidal residue is dissolved in 2 per cent 
acetic acid, filtered, a few crystals of potassium nitrate added, shaken 
until dissolved and the solution allowed to stand. The crystals of jervin 
nitrate which deposit on standing are filtered, washed with a little water 
and then treated with chloroform and a little dilute ammonia. The jervin 
dissolves in the solvent and may be obtained by evaporating. If the 
analyst can obtain sufficient material, this test will furnish the best evi- 
dence of the presence of Veratrurn "in a medicinal preparation. 



CHAPTER IX 

ALKALOIDS WITH NO PYMDIN NUCLEUS AND THOSE OF 
UNKNOWN COMPOSITION 

COLCHICIN, C 16 H 9 (NHCOCH3)(OCH 3 ) 3 (COOCH3) 

The meadow saffron, Colchicum autumnale L. (Liliacese), contains 
the alkaloid colchicin and probably some of its degradation products. 
The parts of the plant used commercially are the bulbous root, called 
the corm, and the seed. The alkaloid is present in amounts varying from 
0.2 — 0.5 per cent. 

Colchicum extract and the alkaloid colchicin have long been used for 
relieving gout and rheumatism, and should always be looked for in prepa- 
rations recommended for these ailments. Wine of colchicum is exten- 
sively employed in some localities, and one of the most widely advertised 
proprietaries is a globule containing colchicin dissolved in methyl salicylate. 
Colchicum extract is combined with Hyoscyamus, colocynth, and calomel, 
and also with aconite. Colchicin is often combined with salicylates in 
liquid form, also with potassium iodide, digitalin, Phytolacca, codein, 
quinin, and opium. 

Colchicin is the methyl ester of colchicein or acetotrimetbylcolchi- 
cinic acid, and on heating with mineral acids it is readily split up into 
methyl alcohol and colchicein. The latter, on heating with hydrochloric 
acid, lose* an acetyl group as acetic acid, and then three methyl groups 
as methyl chloride, leaving colchicinic acid, CioHiiN(OH) 3 (COOH). Col- 
chicein has the composition CisH^NHCOCHsXOCHsMCOOH). 

Colchicin is a weak base and one of the few yellow alkaloids, resembling 
berberin in this respect, but differing from it in being completely removed 
from its solutions even when acid, by chloroform. As usually obtained 
it is a resinous mass which melts with decomposition at about 140-145°. 
In its crystalline form it melts 120°. It is readily soluble in alcohol and 
water, and quite readily in chloroform and benzol, but is difficultly soluble 
in ether and practically insoluble in petroleum ether. Its aqueous solu- 
tion is lsevorotatory. Its solution in dilute acids gives precipitates with 
most of the alkaloidal reagents except platinic chloride. In aqueous solu- 
tion chlorine and bromin water give yellow precipitates which dissolve 
in ammonia with an orange color. 

281 



282 ALKALOIDAL DRUGS 

Colchicin dissolves in concentrated sulphuric acid to a yellow solution, 
and on adding a drop of nitric, the color changes to green, blue, violet, 
wine red, and finally green; addition of concentrated sodium hydroxide 
in slight excess then gives an orange red. It dissolves in nitric acid with 
a deep purple or bluish color. It gives a yellowish-green solution with 
ammonium vanadate; a green color soon fading with sulphuric acid and 
bichromate; and with formaldehyde sulphuric acid the crystals become 
reddish and the liquid yellow. An aqueous solution of colchicin heated 
on the steam-bath for one-half hour with 5 drops of 20 per cent hydro- 
chloric acid and subsequently treated with 3 to 5 drops of ferric chloride 
solution will develop a green color, and on cooling and shaking out with 
chloroform the latter will separate either yellowish or permanganate red, 
depending on the amount of colchicin present. If the colored liquids are 
too opaque, the mixture must be diluted with water. The red tint will 
not appear unless the amount of colchicin be over 2 milligrams. 

It combines with chloroform to form opaque needles with a mother- 
of-pearl luster. This substance loses chloroform when heated to 100° C. 
or when warmed with water It is now being marketed as a medicinal 
product. Colchicin also forms a crystalline compound with ether. 

A non-poisonous substance giving many of the reactions for colchicin 
has been found among the normal constituents of beer, being apparently 
derived from .hops. Putrefying cadavers yield substances which bear a 
close resemblance to colchicin, and might easily be mistaken for this alka- 
loid in toxicological w T ork. 

Colchicein, its first degradation product, forms shining needles with 
JH2O. The water may be driven off at 140-150° and the anhydrous 
substance then melts 160-170°. It is slightly soluble in cold water, readily 
soluble in alcohol and chloroform, and almost insoluble in ether and benzol. 
On account of the ease with which colchicin is hydrolyzed, it is probable 
that colchicein is present to a greater or less extent in most of the colchicin 
residues obtained in analytical work. It is soluble in alkalies and alkali 
carbonates, and with acids forms yellow solutions. 

Colchicin may be readily detected in the mixtures in which it is com- 
monly employed on account of its solubility in chloroform from a neutral 
or acid solution. It will seldom if ever be found combined with berberin, 
and if the latter is present, the greater part will remain in solution until 
the final shake-out with alcohol — chloroform according to the regular 
scheme. When colchicin occurs combined with Hyoscyamus, aconite, 
opium, codein, or quinin it will be completely separated from all of the 
other alkaloids except possibly narcotin, narcein, and papaverin, when 
the acid solution of the crude alkaloids is shaken out with chloroform. 
The presence of the above mentioned opium alkaloids in the residue will 
be at once apparent on adding formaldehyde-sulphuric acid. When col- 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 283 

chicin occurs mixed with salicylates, the salicylic acid will of course appear 
in the chloroform residue from an acid shake out; if the residue is then 
dissolved in chloroform and the solution shaken out with sodium hydroxide, 
the salicylic acid will be completely removed. In some cases before sub- 
jecting a colchicin residue to the color tests and other reactions for its 
identification, it will be advantageous to purify the alkaloid by precipi- 
tating, as the iodine compound as described under the assay of colchicum. 

The preliminary treatment of the samples in which it is desired to 
find colchicin, should follow the usual lines customarily employed when 
working with organic mixtures. An exception should be made, however, 
in the case of the globules of colchicin and methyl salicylate. The medica- 
ment should be washed out with petroleum ether, poured into a separatoiy 
funnel, and then shaken out with dilute hydrochloride acid to remove the 
colchicin. The alkaloid can be recovered from the acid by agitation with 
chloroform. 

Quantitative Methods. — The separation and determination of col- 
chicin in wine of Colchicum and in Colchicum preparations generally may 
be carried out according to the procedure described under the assay of 
colchicum. If the sample is a liquid, 25-50 mils should be taken as a 
sample, the bulk of the alcohol evaporated on the water-bath and the 
residual solution transferred to a separator with water and petroleum 
ether, then made slightly acid with hydrochloric acid and the colchicin 
extracted with chloroform and purified. After removing the crude col- 
chicin the acid aqueous liquid can be set aside and later treated with 
excess of ammonia and any atropin, aconitin, codein, quinin, or morphin 
determined by shaking out with the proper solvents. 

If salicylates are present the procedure must be modified by dissolving 
the crude colchicin in chloroform, transferring to a separator and shaking 
out two or three times with dilute sodium hydroxide to remove the salicylic 
acid. The alkaline liquid is then washed once with fresh chloroform, the 
latter added to the chloroform containing the colchicin, the whole filtered 
and evaporated. 

If the sample is a pill or tablet 10-20 units should be ground in a mor- 
tar and extracted four to five times with alcohol, the alcoholic solution 
filtered, 20 mils water added and after evaporating most of the alcohol, 
the assay continued as described above. 

ASSAY OF GLOBULES OF COLCHICIN AND METHYL SALICYLATE 

For assaying globules of colchicin and methyl salicylate, a dozen or 
more of the globules should be pierced and the contents poured into a 
weighing tube. A weighed quantity of the liquid is then transferred to 
a separator with petroleum ether, and the mixture shaken out with dilute 



284 ALKALOIDAL DRUGS 

hydrochloric acid until the colchicin is entirely removed, four extractions in 
general being sufficient. The colchicin may then be recovered from the acid 
by shaking out with chloroform. It it is desired to determine the amount 
of methyl salicylate in the petroleum ether solution, after the acid treat- 
ment, it is transferred to a flask of about 200 mils capacity, 50-100 mils 
of alcoholic potash added, and the contents boiled under a reflux condenser 
until the methyl salicylate is entirely saponified. The alcohol is then 
evaporated, the solution poured into a separator, the salicylic acid set 
free by mineral acid and shaken out with ether from which solution it 
may be determined by titration with standard alkali, or by removing with 
sodium bicarbonate and precipitating with iodine, the details of which 
are described under salicylic acid, page 676. The factor for methyl salicy- 
late is 1.1014. 

THE XANTHIN BASES 

Xanthin, C5H4N4O2. 
Caffein, C 8 Hi N4O 2 . 
Theobromin, C 7 H 8 N 4 02. 
Theophyllin, C 7 H 8 N 4 02. 
Hypoxanthin, C5H4N4O. 
Guanin, C5H5N5O. 
Adenin, C5H5N5. 

These bases occur naturally in some or all of the following : tea, coffee, 
cocoa, Paraguay tea or mate, guarana, and cola. 

Tea leaves contain all except theobromin and guanin, the caffein com- 
prising from 2 to 2J per cent. 

Cocoa beans (Cacao seed) contain from 1 to 4 per cent of theobromin 
and a small amount of caffein-: 

Coffee leaves contain 1 to 3 per cent of caffein alone, and the beans 
from .5 to 2.5 per cent caffein alone. 

Paraguay tea contains from 1 to 2 per cent of caffein alone. 

Guarana contains as high as 5 per cent of caffein alone. 

Cola contains from 2 to 3 per cent of caffein and a little theobromin, 
about .02 per cent. 

The last four bases are found in the seeds, buds and roots of a large 
number of plants, and also occur widely distributed in the animal king- 
dom, having been observed in almost all the organisms of the higher animals 
and are probably decomposition products of nuclein. They are deriv- 
atives of purin, C5H4N4. Their constitutional characteristics have been 
developed by Fischer. 

Purin is also the mother substance of uric acid. This latter is a tri- 
oxypurin and from it purin may be prepared. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 



285 



The constitution of purin is seen by the following structural formulae: 
Derivatives of both forms are known. 



H 

N C— NH 



HC 



CH 

C— N 



\ 



N 



or 



H 

N C=N 



HC 



\ 
CH 

/ 
C— NH 



w 



The most important member of this group is camein, and it will be 
found very extensively in medicinal preparations. Theobromin present 
in cocoa will also be met with to some extent, but the other bases will 
seldom be found except in meat products and preparations of this type. 



Xanthin 


/ c \ 

HN C— NH 

\ 



CH 



OC C— N 

\ N / 
H 

2-6 dioxypurin 

Xanthin occurs naturally in tea leaves, the juice of the beet, shoots 
of lupine and barley, and is not liable to be met with to any extent in drug 
analysis. It is usually present in meat products and it is in preparations 
of this type that it might be found. 

It separates from its aqueous solution as a white powder, and when 
heated it decomposes above 150° without melting, and evolves carbon 
dioxide, ammonia, and hydrocyanic acid. It is almost insoluble in cold 
water, and very little soluble in hot water; insoluble in alcohol and ether. 
It is a weak, monoacid base, has acid properties and unites with bases 
to form salts containing two equivalents of the metal. These salts are 
very unstable, being decomposed by carbon dioxide and water. Xanthin 
is soluble in caustic alkalies, but is precipitated by adding an acid or even 
passing carbon dioxide gas through the mixture. It is dissolved by warm 
ammonia, which distinguishes it from uric acid. Mercuric chloride pre- 
cipitates xanthin in very dilute solutions. Cupric acetate produces no 
precipitate in the cold, but on heating a flocculent apple-green precipitate 



286 ALKALOIDAL DRUGS 

is produced. An ammoniacal solution of xanthin gives precipitates with 
zinc chloride, calcium chloride, and lead acetate. 

On treatment with potassium chlorate and concentrated hydrochloric 
acid it is oxidized to urea and alloxan, and on evaporating the solution to 
dryness and exposing to the fumes of ammonia a bright pink color develops. 
This is known as the murexide reaction. 

Xanthin dissolves in hot nitric acid without evolution of gas. On 
careful evaporation of the solution a yellow residue remains, which turns 
reddish yellow on addition of caustic potash or soda, and on subsequent 
heating becomes reddish violet. If ammonia be substituted for the fixed 
alkali, no violet coloration is obtained. This test distinguishes xanthin 
from uric acid, which gives the characteristic murexide reaction when 
similarly treated. 

If solid xanthin be sprinkled on a solution of caustic soda mixed with 
bleaching powder, each particle becomes surrounded with a dark ring or 
scum, which rapidly becomes brown and then disappears. 

Xanthin may be converted to theobromin by treating its lead salt 
with methyl iodide and heating to 100°. 

C 5 H 2 N402Pb+2CH3l = C 5 H2N40 2 (CH3)2+Pbl2 

It may be converted to caffein by heating it in aqueous alkali with 
methyl iodide. 

C 5 H 4 N402+3CH3l+3KOH = C5HN402(CH 3 )3+3KI+3H20 

In the general run of drug assaying it is doubtful if one would be called 
upon to make a quantitative estimation of xanthin bases other than 
caffein and theobromin, but in case it becomes necessary to determine 
these bodies, attention is directed to the following method: 

Xanthin Bases. (Schittenhelm's Method.) 1 — Dissolve from 3 to 5 
grams of the extract in 100 mils of water, transfer to a large evaporating 
dish, and add 500 mils of a 1 per cent solution of sulphuric acid. Heat 
on the water-bath for four or five hours, finally evaporating to a volume 
of from 75 to 100 mils, neutralize with potassium hydroxide, using litmus 
paper as an indicator. Transfer to a beaker, add 15 mils of a 15 per cent 
solution of sodium bisulphate and from 15 to 20 mils of a 15 per cent solu- 
tion of copper sulphate, cover with a watch-glass, and let stand overnight. 
Filter and wash with dilute copper sulphate. Return the precipitate to 
the original beaker, add sodium sulphide, acidify with acetic acid and 
warm on the steam-bath. Filter hot and wash with hot water. Treat 
the filtrate with 10 mils of 10 per cent hydrochloric acid and evaporate it 
on the steam-bath to about 10 mils. Filter and wash, make ammoniacal 
1 Bull. 90, U. S. Dept. of Agriculture, page 129. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 287 

and add in slight excess a 3 per cent solution of ammoniacal silver nitrate. 
Let stand overnight, filter, wash out all ammonia carefully, and determine 
nitrogen in the precipitate. The result is the nitrogen of the xanthin 



Caffein 
O 

/ C \ /CH 3 

CH 3 N C— N<^ 

CH 

C— N^ 

\ N / 
CH 3 

1-3-8 Tri Methyl Xanthin or 
1-3-8 Tri Methyl — 2-6 Dioxypurin 

Caffein was discovered in the coffee berry in 1820, and it occurs in this 
plant in combination with citric and tannic acids. It occurs also in tea, 
guarana, Paraguay tea, cola nut, and the seeds of cacao. The base is 
present in the plants in the free state to some extent, but it also occurs 
combined with acids and probably also in the form of glucosides. This 
renders a simple, complete extraction of caffein from drug extracts dif- 
ficult if not impossible, and it becomes necessary to treat the products 
with acids or alkalies in order to effect hydrolysis or separation from the 
plant acids. 

In medicinal preparations, particularly of the headache mixture type, 
caffein will be found in the alkaloidal form. Guarana extract will be 
met with both in the liquid and solid form. Cola preparations are found 
quite extensively on the market, but extracts of coffee or tea will be met 
with only sparingly. Caffein and preparations of guarana and cola occur 
in products which are designed to cause stimulation and in tonics for the 
nervous system. Headache mixtures nearly always contain caffein, and 
it will be found in diuretic compounds and in some heart tonics. It is 
used to a large extent as an ingredient of popular beverages. 

Caffein and caffein-containing drugs will be found in products of the 
following types: 

Elixir celery compound, containing celery seed, coca, kola, and often 
Viburnum prunif olium ; elixir kola compound, containing celery seed, 
kola, and coca; kola wine and kola cordial; elixir celery and guarana; 
elixir acetanilid compound, containing acetanilid, caffein, sodium bromide, 
codein, and Gelsemium; elixir migraine, containing acetanilid, caffein, 
and sodium bromide; liquid headache mixtures contain caffein together 
with acetanilid, acetphenetidin, antipyrin, bromides, and often aromatic 
spirit of ammonia; pills are marketed containing extract of kola and 



288 ALKALOIDAL DRUGS 

extract of guarana, but most of the caffein bearing-preparations of 
this kind contain the alkaloid caffein; cardiac pills containing caffein, 
Digitalis, glonoin and Strophanthus, and sometimes codein; compressed 
tablets for relieving headache contain caffein and acetanilid, and often 
acetphenetidin or antipyrin, or some combination of these substances 
with bromides and sodium bicarbonate; migrain tablets contain caffein 
and camphor monobromate; neuralgic tablets contain caffein with Hyos- 
cyamus and morphin. 

Caffein is a feeble base, but forms definite compounds with mineral 
acids, which, however, are easily broken up in aqueous solutions. It 
crystallizes in fleecy masses of long, flexible, white crystals, having a silky 
luster, odorless, with a bitter taste, and permanent in the air. Its reac- 
tion is neutral to litmus. 

It is soluble at 15° C. in 80 parts of water, 33 parts of alcohol, seven 
parts of chloroform, and about 550 parts of ether. It is readily soluble 
in boiling water, chloroform, alcohol, amyl alcohol, and benzol, less sol- 
uble in ether, and only slightly in carbon bisulphide and petroleum ether. 

It does not evaporate with the vapor of water, and undergoes no appreci- 
able change at 100° C. except that its water of crystallization, 1 molecule, 
is expelled. At 100° it volatilizes very gradually, and at a high temper- 
ature it sublimes unchanged. At 229° C. it melts to a colorless liquid. 
It readily undergoes decomposition when boiled with limewater, but decom- 
position is insignificant when boiled with magnesium oxide and water, and 
no change occurs with lead oxide. 

It may be oxidized by nitric acid or by hydrochloric acid and potas- 
sium chlorate, the products of oxidation including amalic acid, which on 
subsequent treatment with ammonia goes over to murexoin, which has a 
brilliant purplish-pink color. Uric acid and oxidizing agents give allo- 
xanthin, C8H 6 N408, and with ammonia this latter is converted into murex- 
ide, NH4C8H4N5O6. Theobromin and xanthin give a reaction similar to 
caffein. The purple coloration in case of caffein and theobromin is decolor- 
ized by caustic alkali, but that due to uric acid is changed to blue. 

An aqueous solution of caffein is not precipitated by potassium-mer- 
curic iodide test solution. This is also true of theobromin. A neutral 
aqueous solution is not precipitated by a solution of iodin and potassium 
iodide, but in, an acid solution, caffein is precipitated quantitatively. Its 
solution in water (1 to 200) gives an abundant precipitate on adding a satu- 
rated solution of mercuric chloride. More dilute solutions give less immedi- 
ate precipitate. Tannic acid gives a precipitate soluble in excess of the 
reagent. Potassium-bismuth iodide precipitates caffein from moderately 
dilute solutions after a time. Phosphomolybdic acid gives a yellow pre- 
cipitate, soluble in warm sodium acetate solution, and depositing free 
caffein on cooling. Platinic chloride and hydrochloric acid added to a 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 289 

concentrated solution gives an orange-red precipitate, soluble in 20 parts 
of cold and smaller amounts of warm water, crystallizing again on cooling. 

The solubility of caffein in water is increased by the presence of cer- 
tain substances, such as sodium bromide, sodium benzoate, sodium cin- 
namate, sodium salicylate, and antipyrin. 

Caffein may be completely removed from an acid aqueous solution 
by shaking out with chloroform. 

Caffein is removed from an aqueous solution by charcoal, but when 
dissolved in chloroform the solution may be shaken with charcoal with- 
out any absorption of the base. Lead sulphide will carry down caffein 
when precipitated from solutions clarified by lead acetate. 

Caffein may be separated from theobromin by treating the mixed alka- 
loids with cold benzol, in which theobromin is practically insoluble. 

QUANTITATIVE DETERMINATION OF CAFFEIN 

The methods for the determination of caffein in fluid extracts of guarana 
and kola have already been described. 

In all cases where caffein is present wholly or partly in the form of a 
drug extract caution must be observed that the caffein compounds are 
thoroughly broken up so that the alkaloid will be completely extracted. 

Many methods for the estimation of caffein in tea or coffee have been 
published and most of them are unsatisfactory and unreliable. The 
Association of Official Agricultural Chemists require the use of the modi- 
fied Stahlschmidt method in official work for determining the caffein in 
tea, and the Gorter method for coffee. 

Modified Stahlschmidt Method. — Weigh 3.125 grams of the finely 
powdered sample into a 500-mil flask, add 225 mils of water (this volume 
will shrink to about 200 mils by boiling), attach a reflux condenser and 
boil for two hours. Add 2 grams of dry basic lead acetate and boil ten 
minutes more. Cool, transfer to a 250-mil graduated flask, fill to the 
mark, filter through a dry filter, measure 200 mils of the filtrate into a 
250-mil graduated flask and pass hydrogen sulphide through it to remove 
the excess of lead. Make the solution up to the mark and filter through 
a dry filter. Measure 200 mils of this filtrate into an evaporating dish 
and concentrate to about 40 mils. Wash the concentrated solution with 
as little water as possible into a small separatory funnel and shake out 
four times with chloroform, using 25, 20, 15, and 10 mils, respectively. 
If any emulsion forms, break it up with a stirring rod and run the separated 
portions of chloroform through a 5-c.m. filter paper into a small, tared 
Erlenmej^er flask. Evaporate off the chloroform on the steam-bath, or 
recover the chloroform by attaching the flask to a condenser and dis- 
tilling to a small volume. Dry the fine, white crystals of caffein to con- 



290 ALKALOIDAL DRUGS 

stant weight at 75° C. Test the purity of this residue by determining 
nitrogen and multiplying by the factor 3.464. 

Gorter Method. — Moisten 11 grams of finely powdered coffee with 3 
mils of water, allow to stand thirty minutes and extract with chloroform 
for three hours in a Soxhlet extractor. Evaporate the extract, treat the 
residue of fat and caffein with hot water, filter through a cotton plug and 
moistened filter paper and wash with hot water. Make up the filtrate 
and washings to 55 mils, pipette off 50 mils and extract four times with 
chloroform. Evaporate the chloroform extract in a tared flask, dry the 
caffein at 100° C, and weigh. Transfer the residue to a Kjeldahl flask 
with a small amount of hot water and determine nitrogen. To obtain 
the weight of caffein multiply the result by 3.464. 

From most of the alkaloids with which it may occur combined, caffein 
may be separated by taking advantage of the fact that it can be removed 
from acid solution by chloroform, the other bases being retained. This, 
however, is not the case when acetanilid, acetphenetidin, and antipyrin 
are present, and special methods of separation have been provided which 
will be found on pages 795, 837 and 857. 

In the case of liquid preparations containing caffein in the form of 
base, or when present in the form of kola, guarana, coffee or tea; or com- 
bined with alkaloids such as cocain, morphin, strychnin, and atropin; 
weigh or measure accurately the sample, transfer to a medium sized evapo- 
rating dish, add ammonia and digest for four hours and evaporate over 
steam-bath until no further diminution in volume takes place. Treat 
the residue with alcohol, warm, then cool and decant washings into another 
evaporating dish. Repeat the process four or five times if necessary 
should the residue contain much gummy material. Add water to the 
alcoholic solution, and then evaporate over steam-bath until all alcohol 
is driven off. Transfer to a separatory funnel, washing out dish with 
water and render the solution slightly ammoniacal. Shake out with four 
successive portions of chloroform using 15 to 20 mils each time. The 
chloroform now contains all the caffein and if any other base is present 
this is also dissolved, morphin of course to a very limited extent. Now 
shake out with three successive portions of 2 per cent sulphuric acid, which 
will remove all the bases except caffein and preserve the acid solution. 

Filter the chloroform solution into a tared dish, washing the funnel, 
filter paper, inside of funnel, and stem of funnel with chloroform and evapo- 
rate to dryness at 100°. If the residue of caffein is colored, or con tarns 
grease or has much odor it should be dissolved in dilute hydrochloric acid, 
transferred to a flask, and an excess of strong solution of iodine in potassium 
iodide added. Rotate the flask until the caffein iodin compound agglom- 
erates and let stand overnight. Filter, wash precipitate once with iodin 
solution, discarding washing and not attempting to remove the last por- 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 291 

tion of precipitate from flask in which precipitation was made. Pour 
a solution of sulphurous acid over filter or place a crystal of sodium sul- 
phite on the filter, add water and 1 to 2 mils of hydrochloric acid and run 
the liquid into the flask in which the original precipitation was made; 
wash filter paper with sufficient of the liquid to decompose the iodine 
compound and then place filter paper in flask and heat for ten to fifteen 
minutes over the steam-bath. Cool, filter into separatory funnel, wash 
out flask three times with water. Render ammoniacal and shake out 
three times with 15- to 20-mil portions of chloroform. Run chloroform 
through filter into a tared dish, using precautions of washing with chloro- 
form as above mentioned. Evaporate to constant weight at 100°. 

In some instances a dye stuff will stay with the caffein, but this may 
be removed by shaking the chloroform solution with a strong solution 
of sodium bisulphite. 

The other alkaloids having been separated by the above mentioned 
method by shaking out with acid can now be determined. The details 
and precaution to be observed are described under the particular alkaloid 
in question. 





Theobromin 





HN C— N< 




CH 


OC C— N^ 


3-7 dimethyl 2 


CHa 

-6 dioxypurin or 3-7 dimethylxanthin 



Theobromin occurs in cacao beans combined with malic acid. It also 
occurs in small amounts in kola nuts. 

Theobromin is a diuretic and a nerve stimulant and its compounds 
with benzoates, salicylates, etc., have a limited use in medicine. Urocitral 
is a mixture of molecular amounts of theobromin and sodium citrate; 
agurin of theobromin and sodium acetate ; uropherin B of theobromin and 
lithium benzoate; uropherin S of theobromin and lithium salicylate. 
Iodotheobromin consists of 40 per cent theobromin, 21.6 per cent sodium 
iodide and 38.4 per cent sodium salicylate. 

Chocolate is used in some preparations in order to make them palatable 
and the analyst will probably find theobromin here. Its presence or 
absence will also be valuable evidence in determining whether many of 
the so-called " chocolate-coated tablets " are actually covered with choco- 
late or only iron oxide encased in sugar. 



292 ALKALOIDAL DRUGS 

Theobromin crystallizes in the anhydrous state and forms microscopic 
needles, melting 329-330° C. in a closed tube. When heated exposed 
to the air it sublimes without melting at 290-295° C. 

It is soluble in amyl alcohol, fairly soluble in chloroform, alcohol and 
water when hot, slightly soluble in benzol, ether, cold water, and alcohol, 
and insoluble in petroleum ether and carbon tetrachloride. It is soluble 
in acids and precipitated by alkalies, but soluble in excess of caustic alkali 
or ammonia. It is wholly extracted by chloroform from its solutions in 
caustic alkalies. 

It is a weak monoacid base, neutral, and its salts are decomposed by 
water. It does not combine with alkyl iodides. It possesses acid prop- 
erties and forms definite salts, the sodium and barium salts having been 
studied. 

Theobromin gives a white crystalline precipitate with mercuric chloride, 
sparingly soluble in water and alcohol. 

It forms with silver nitrate a definite and insoluble compound, 
C7HsN402AgN03, which is only sparingly soluble in water and may be 
dried unchanged at 100° C. 

With solution of sodium phosphotungstate it gives in acid solution 
a yellow precipitate. This may be mixed with sodium carbonate or mag- 
nesium oxide, dried, exhausted with chloroform and the theobromin 
recovered. 

When boiled with concentrated barium hydrate solution or alkalies 
it .yields no product similar to caffeidin. 

Theobromin gives with oxidizing agents and ammonia the same color 
reactions as caffein. 

If 0.05 gram theobromin is treated with 3 mils water and 6 mils sodium 
hydroxide solution, and to the mixture 1 mil ammonia and 1 mil 10 per 
cent silver nitrate added, solidification takes place on shaking, the mass 
will liquefy at 60° C, and on cooling a transparent jelly results which 
will withstand the action of light for a week or more. Caffein does not 
give this test, and theobromin may be separated from caffein by precipi- 
tating it as the silver nitrate compound. 

Estimation of Theobromin 

Method of Decker as Modified by Welman. — Boil 5 grams of 
powdered cacao seeds which have not been freed from fat, or 10 grams 
of chocolate, for an hour in a large Erlenmeyer flask under a reflux con- 
denser with 5 grams of magnesium oxide (calcined magnesia) and 300 mils 
of water. Let the flask stand upon a boiling water-bath until the sus- 
pended matter has settled and then pour the hot, supernatant liquid 
through an asbestos filter. Wash the residue in the flask twice with 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 293 

200-mil portions of boiling water. Pour the clear liquid through the same 
asbestos filter. It is advisable to use a water pump in filtering. Boil 
the residue again for an hour under a reflux condenser with 2 grams of 
magnesium oxide and 300 mils of water, decant, and filter. Mix all the 
filtrates with ignited sea sand and evaporate to dryness upon the water- 
bath. Reduce the residue in a hot mortar to as fine a powder as possible, 
extract three or four times in an Erlenmeyer flask for thirty minutes with 
70-mil portions of chloroform and filter hot. Distill each portion of chloro- 
form upon the water-bath and use the solvent again. Pass a gentle stream 
of air through the flask, until there is no odor of chloroform. Dissolve 
the residue in 10 per cent ammonium hydroxide solution and filter. Evapo- 
rate the nitrate to dryness in a weighed platinum dish, dry the residue 
to constant weight and deduct the weight of ash from the weight of total 
alkaloids. Caffein and theobromin can be separated by cold benzene, 
theobromin being soluble only to the extent of 1 : 100,000, whereas caffein 
passes easily into solution. 

Method of Kunze. — Heat 10 grams of powered cacao-seeds twenty 
minutes with 150 mils of 5 per cent sulphuric acid. Filter while hot and 
add excess of sodium phosphomolybdate to the warm filtrate. Set aside 
for a day and wash the precipitate upon a filter with 5 per cent sulphuric 
acid. Decompose the moist precipitate, containing theobromin, in a large 
beaker with barium hydroxide. Precipitate excess of barium hydroxide 
by carbon dioxide, evaporate the mixture to dryness upon the water-bath 
and extract the well-dried residue under a reflux condenser with boiling 
chloroform. Evaporate the chloroform solution in a weighed flask and 
dry the residue to constant weight. This residue consists essentially of 
theobromin mixed with some caffein. This gives the weight of total alka- 
loids. To estimate theobromin, dissolve the residue in water containing 
ammonia, add excess of N/10 silver nitrate solution in known quantity 
and heat to boiling. This will precipitate the silver salt of theobromin 
(CyHyN-iCbAg- IIH2O) free from caffein. Determine excess of silver 
in an aliquot portion of the measured filtrate by titration with N/10 
sulphocyanate solution. Caffein does not form a silver compound. To 
determine the corresponding quantity of theobromin, multiply the weight 
of silver in the precipitate by 1.66. 

Determination of Theobromin and Separation from Caffein. (Brun- 
ner and Lewis.) — The substance, such as coffee, kola, cocoa, or mate, 
is boiled for thirty minutes, with 500 mils of water, under a reflux con- 
denser. The solution is then precipitated with freshly prepared lead 
hydroxide, until colorless, heated again to boiling for fifteen minutes, and 
filtered. The residue is washed twice with 500 mils of water, the filtrate 
and washings being reduced, by evaporation, to a volume of 500 mils. 
Carbon dioxide is led through the boiling solution, the precipitated lead 



294 



ALKALOIDAL DRUGS 



carbonate is filtered off, and the filtrate evaporated on the water-bath, 
after adding some quartz sand. The residue obtained is extracted for 
eight hours with ether in a Soxhlet apparatus. After distilling off the 
ether, the residue is boiled out three times with 50 mils of water, and 
filtered, when cooled to 50° C. On evaporating and drying at 80° C, 
the two alkaloids are obtained as a white ash-free product. 

Separation. — The mixed alkaloids are dissolved in hot water, pre- 
cipitated with silver nitrate, the precipitate redissolved in 2 to 3 mils of 
ammonia, and the solution warmed to expel the latter, dust and a strong 
light avoided. After cooling to 30° C, the precipitated silver-theobromin 
is collected on a weighed filter, washed, and dried at 100° C. The sub- 
stance has the formula CyHyAg^CV 

The filtrate is treated with sodium chloride, filtered and evaporated 
on the water-bath. The caffein is extracted from the residue with ether, 
the latter is evaporated, and the alkaloid dried at 100° C,. and weighed. 






Theophyllin 



CH 3 — N 





/ c \ 



oc 



I 



C— NH 

\ 
CH 

C— N 



CH 3 

1-3 dimethyl 2-6 dioxypurin 



Theophyllin is an isomer of theobromin and occurs in tea leaves. It 
is also made synthetically and marketed under the name of Theocin. 

It is a powerful diuretic, and is also used in cardiac affections and 
dropsy. 

It crystallizes in plates, melting at 264-268° C, somewhat soluble in 
cold but readily in boiling water, soluble in chloroform, little soluble in 
alcohol, and insoluble in ether, 

It is a weak monoacid base and forms readily soluble potassium, 
sodium, and ammonium salts, and is not removed readily by solvents from 
alkaline solution. 

It forms a crystalline hydrochloride, nitrate, chloroplatinate, auro- 
chloride, and mer euro-chloride. When evaporated with chlorine water, 
theophyllin yields a scarlet residue which is changed to violet on addition 
of ammonia. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 295 

The silver derivative, CyH^AgN^, is obtained as an amorphous pre- 
cipitate on adding silver nitrate to an aqueous solution of theophyllin. 
It crystallizes from hot ammonia, and dissolves readily in nitric acid. The 
methyl derivative, C7H7MeN4C>2, prepared by heating the last substance 
with methyl iodide and methyl alcohol, melts at 229°, and is identical 
with caffein. 

When a solution of theophyllin in sodium hydroxide is treated with a 
solution of 0.5 per cent sulphanilic acid and 5 per cent hydrochloric in 
water, followed by a few drops of 0.5 per cent solution of sodium nitrite, 
a red coloration is produced. Caffein and theobromin do not respond to 
this reaction. 

It gives a precipitate with tannic acid soluble in excess of the reagent. 

Theophorin is a mixture of molecular amounts of theophyllin and 
sodium formate. 

Hypoxanthin or Sarcin 

C-oxypurine 

This body differs from xanthin only in possessing one less oxygen atom. 

It occurs in both the animal and vegetable kingdoms and in the former 
is probably a decomposition product of nuclein. 

It is present in the seeds of the lupine, barley, mustard, black pepper, 
vetch, gourd, alfalfa, cloves, in wheat bran, potatoes, sugar-beets, and tea. 

It forms microscopic needles decomposing without melting at 150° C. 
Little soluble in water; scarcely soluble even in hot alcohol and insoluble 
in ether. 

It possesses both acid and basic properties and combines with one 
equivalent of an acid and two of a base. 

On oxidation with potassium chlorate and hydrochloric acid it gives 
alloxan and urea the same as xanthin. 

It forms crystallizable salts with acids and the microscopic appear- 
ance of the nitrate and hydrochloride are characteristic. 

The silver oxide compound, Ag20CoHoN40. is formed as a gelatinous 
precipitate on adding ammonio-nitrate of silver to an ammoniacal solu- 
tion of the base. It is insoluble in ammonia, unless used in great excess, 
and it dissolves with difficulty in boiling nitric acid; 1.10 sp. gr. On 
cooling a compound of the formula, CsHs^OAgNOs, separates in crystals 
having a characteristic form under the microscope. The character of 
silver nitrate compound permits the separation of hypoxanthin from other 
bases of the group. 

On treatment with hydrochloric acid and zinc it gives a ruby-red 
coloration on the addition of caustic soda in excess. Adenin gives a red 
color under similar conditions. 



296 



ALKALOIDAL DRUGS 



Guanin 

2-amido 6-oxypurin 

Guanin occurs in the seeds of several leguminous plants, in those of 
the gourd, in the sugar-beet and in cane sugar. 

It crystallizes from ammonia in needles or small plates which are 
insoluble in water, alcohol, or ether. It is neutral and dissolves in both 
acids and alkalies to form salts in which it functionates on the one hand 
as a diacid base and on the other as a dibasic acid. 

It may be heated to 200° without change. 

Guanin is distinguished from xanthin and hypoxanthin by its insolu- 
bility in hot dilute ammonia. 

It gives a highly insoluble precipitate with picric acid. 

It gives precipitates with potassium bichromate and potassium ferri- 
cyanide, differing thereby from xanthin and hypoxanthin. 

Its hydrochloride and nitrate have characteristic forms when viewed 
under the microscope. 



Adenin 

6-amidopurin 

Adenin occurs in the pancreas of the ox, in tea, and in sugar-beets. 
It is formed during the decomposition of nuclein by sulphuric acid. 

It crystallizes in long needles with one molecule of water. The anhy- / 
drous alkaloid melts without decomposition at 360-365° C. 

It is readily soluble in hot water, little soluble in cold water or alcohol, 
and insoluble in ether and chloroform. It is neutral and forms salts with 
one equivalent of an acid or a base. 

Adenin does not give the ordinary color reactions of the xanthin bases, 
but resembles hypoxanthin in giving a red color when treated with hydro- 
chloric acid and zinc and subsequently with an alkali. 

It gives precipitates with potassium ferrocyanide and ferricyanide after 
acidulating with acetic acid. With chromic acid it gives a crystalline 
compound, and with copper sulphate an amorphous grayish-blue pre- 
cipitate. 

Adenin is very completely precipitated by copper sulphate in presence 
of a reducing body and by using sodium thiosulphate and operating in 
cold solutions it may be separated from hypoxanthin. 

t!!arnin, C7H8N4O3, Vernin, CieB^oNgOg, Pseudoxanthin, C4H5N5O, 
Heteroxanthin, C6H6N4O2, andr^Baraxanthin, C7H8N4O2, are of no special 
interest to the drug chemist. 

With the exception of caffem, theobromin, and theophyllin, all of the 
xanthin bases are insoluble in ether and chloroform. 

They all give white precipitates with phospho-molybdic acid, mer- 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 297 

curie chloride, and ammoniacal lead acetate, and guanin and adenin are 
very perfectly precipitated by picric acid. 

A general reaction of the xanthin bases (including uric acid) is their 
precipitation from ammoniacal solutions by ammonio-nitrate of silver, as 
a gelatinous compound of the base with agentic oxide. The xanthin com- 
pound contains C5H4N402Ag20. The precipitates are usually insoluble 
in ammonia, unless concentrated and used in large excess, but to ensure 
complete precipitation excess should be avoided. On treating the pre- 
cipitates with dilute nitric acid of 1.10 sp. gr., they are converted 
into compounds of the bases with silver nitrate, xanthin forming 
CsH^^C^AgNOs. These compounds are well-defined crystallizable bodies 
insoluble in water, and, in the cases of Irypoxanthin, carnin, adenin, and 
episarkin, insoluble in nitric acid of the above strength, even on boiling; 
or, at any rate, crystallizing out rapidly on cooling. Guanin, carnin, 
adenin, and episarkin are stated by G. Salomon to behave similarly but, 
according to J. L. W. Thudichum, the silver nitrate compound of guanin 
dissolves tolerably easily in hot dilute nitric acid, and is only very gradu- 
ally deposited on cooling. The compounds of xanthin, heteroxanthin. 
and paraxanthin remain in solution after cooling, which difference of 
behavior permits of their separation from the bases previously mentioned. 
The bases are all completely reprecipitated as their silver-oxide compounds 
on neutralizing the nitric acid solution by ammonia. Heteroxanthin 
and paraxanthin may be separated from xanthin by taking advantage 
of the limited solubility of their sodium salts in caustic soda, and from 
each other by utilizing the sparing solubility of the hydrochloride of 
heteroxanthin. 

Mixtures of the bases with Fehling's solution and hydroxlyamin hydro- 
chloride added all give precipitates except caffein and theobromin. 

CHEMISTRY OF THE BOTANICAL INDIVIDUALS CONTAINING 
THE XANTHIN BASES 

Phytochemical studies of some of the caffein-bearing drugs have 
demonstrated that in the plant the caffein is combined with acidic or 
phenolic-like bodies. These combinations are termed tanoides by some 
authors. In coffee the combination is one of caffein with chlorogenic 
acid and potassium, and in kola and guarana the caffein is united respec- 
tively to kolatin and guaranatin. The caffein in these combinations can- 
not be obtained by extraction directly with chloroform, but only after 
treatment with an aqueous solution. 

Potassium-caffein chlorogenate can be obtained by percolating raw 
coffee with absolute alcohol. The first portion of the percolate is diluted 
with 96 per cent alcohol until a precipitation of shiny material is complete. 



298 ALKALOIDAL DRUGS 

The clear liquid is then mixed with the remainder of the percolate, the 
alcohol recovered in vacuo and the residue evaporated to a syrup in the 
water-bath. The potassium-caffein chlorogenate is allowed to crystallize 
and the crude material recrystallized from 60 per cent alcohol. In order 
to obtain pure chlorogenic acid the substance is dissolved in water, enough 
sulphuric acid added to convert the potassium into sulphate, the liquid 
extracted with chloroform to remove the caffein, and then allowed to 
evaporate spontaneously until the chlorogenic acid crystallizes. The pure 
substance melts 206-207°, slightly soluble in water and ethyl acetate, 
readily in alcohol and acetone, practically insoluble in ether, chloroform, 
and carbon bisulphide. It gives a grass-green color with ferric-chloride, 
and a yellowish red with potassium hydroxide, darkening on exposure. 

KOLA 

Considerable work has been done on the constituents of this drug. 
Knebel first reported kolanin in 1892. * Hilger in 1892 and 1893 verified 
Knebel, the body being apparently a glucoside splitting up under the influ- 
ence of heat or ferments into glucose, caffein and tannin. Carl Schweitzer 
continued and verified this work in 1895. Schlotterbeck published a 
monograph on cola in 1894. A partial analysis of cola was made by 
Knox and Schlotterbeck in 1895. 2 A short historical summary of the 
above work is given by Knox and Prescott. 3 Knox and Prescott investi- 
gated the cafTein compound in cola and determined that it was a cola tan- 
nate of caffein instead of a glucoside. The question arose as to whether 
the tannin in this compound was identical with the free tannin in cola. 
Preliminary investigations seemed to show that there was a difference. 
They finally established the identity of the tannin combined with the 
caffein and the free tannin existing in cola nuts. They do not agree with 
Knebel' s claim that the tannin of the cola is an oxidation product of cola 
red. 4 

Gorris isolated from fresh nuts .3 to .4 per cent of a new constituent 
which he calls kolatin. 5 After a critical review of the constituents Perrot 
and Gorris conclude that only three well-defined bodies have been isolated 
from the drug, namely, caffein, theobromin and kolatin. The last named 
has been obtained from fresh seeds in small white-colored crystals of the 
formula CsHgC^. It is slightly soluble in water and its solution has the 
property of dissolving caffein and theobromin, as solutions of sodium and 
salicylate do; under suitable conditions of high oxidation, it yields cola 

1 Apoth. Zeit., 7, 112. 

2 P. A. P. A., 1895, 334. 

3 P. A. P. A., 1896, 136. 

* P. A. P. A., 1896, 136, 1897, 131 

* Phar. Zeit., No. 11, 1906, 118; P. A. P., A. 1906, 770. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 299 

red. Kolanin is only a mixture, probably mechanical, of cola red and 
caffein. It is not glucosidal and cannot be considered one of the con- 
stituents of the seeds. On drying the nuts kolatin disappears. 1 Gorris 
and Chevalier have studied the physiological activity of kolatin prepared 
from fresh cola nut and find that injected intravenously into warm-blooded 
animals it increases the energy of cardiac contractions and slightly raises 
the blood pressure. It is to a certain extent antagonistic to caffein both 
as regards the action on the muscles and on the central nervous system. 
Hence the powdered seeds sterilized before they were dried have a physio- 
logical action different from that of the dried seeds in which the kolatin 
no longer exists, it having been converted into cola red. 2 
Konig gives the following analysis of cola nut: 

Per Cent 

H 2 11.23 

Nitrogenous material 8 . 34 

Caffein 2.09 

Theobromin 0.023 

Fat 0.52 

Starch 42.72 

Gums and sugar 18 . 94 

Kola red 1.29 

Cellular material 10 . 80 

Ash 3.13 

99.08 
KOLATIN 

Kolatin-caffein has been isolated from the fresh sterilized kola nuts. 
In the dry state this body does not give up its caffein to chloroform, but 
if dissolved in warm water the caffein may be removed by chloroform, 
leaving the kolatin, which crystallizes on cooling. It may be purified by 
recrystallization out of ether. It forms white microscopic needles, melt- 
ing at 148°, slightly soluble in water, very soluble in ethyl and methyl 
alcohol, acetic acid, acetone, slightly soluble in ether and insoluble in 
chloroform and petroleum ether. It has no action on polarized light. 
With ferric chloride it gives a green color, becoming red with ammonia 
or sodium hydroxide and violet with sodium carbonate. 

It is not an acid, it does not neutralize bicarbonates. It reduces 
ammoniacal silver nitrate in cold, and Fehling's solution on heating, and 
is precipitated by lead acetate, potassium bichromate, and copper acetate. 
It is rapidly transformed to a red amorphous body by the action of light, 
heat, or an oxidizing ferment, and continually loses weight when dried in 
a vacuum over sulphuric acid or in an oven at 105°. 

1 Pharm. Gorris, 1908, 31 and P. A. P. A., 1908, 228 
■ P. A. P. A., 1908, 414. 



300 ALKALOIDAL DRUGS 

It has not been settled definitely whether the kola nut contains a com- 
pound of kolatin and caffein similar to the chlorogenate of caffein and 
potassium, or whether the kolatin compound is a complex glucoside. 
Kolatin is a body of the catechin group described as decomposing into 
phloroglucin and protocatechuic acid. Chlorogenic acid acts in similar 
manner. 

Kola nuts contain an oxydase which acts on kolatin during drying and 
produces a " red." The dried nuts, representing the commercial drug 
contain no kolatin, hence this body will not be found in galenical prepa- 
ration. 

ERGOT ALKALOIDS 

Ergot of rye is the sclerotium of Claviceps purpurea (Hypocreacese), 
a fungus having two distinct periods in its life history, an active and a 
resting stage. During the latter it forms a compact mycelium or sclero- 
tium, which replaces the flowers and the grains of rye. It is gathered 
by hand or by threshing. It deteriorates with age, particularly when 
powdered. 

The drug is produced in Russia, Spain, and Germany. Spanish ergot 
consists usually of large grains, having a fine appearance) but often not 
so active as that from other sources. It has a heavy odor which is increased 
when the powder is triturated with warm alkali hydroxide. 

Ergot has a specific action on the uterus and is an indispensable drug 
to the obstetrician. The extract is an important commodity, and many 
modifications are offered, usually under some copyrighted name suggest- 
ive of the derivation of the product, and claiming to be more or less free 
from the inert and irritating substances present in the drug. Sterilized 
aqueous decoctions of the active ingredients free from fat and other princi- 
ples are dispensed in sealed tubes for hypodermic use. In this form of 
package the potency of the drug is retained over a considerable period. 

Solid extract of ergot is a component of emmenagogue formulas which 
contain, in addition, some or all of the following drugs; extract of cotton 
root bark, black hellebore, savine, aloes, ferrous sulphate, and oil of penny- 
royal. It is also combined with Digitalis and quinin; with lupulin, atro- 
pin, Scutellaria, and zinc bromide; with gallic acid and hydrastin; with 
Cannabis sativa, etc. Liquid mixtures contain ergot with Caulophyllum, 
savine, and water pepper; and occasionally some of the drugs mentioned 
above. 

The chemical composition of ergot has been the subject of much study. 
In the aggregate the discovery of a large number of the constituents has 
been reported, and confusion has resulted owing to the numerous desig- 
nations given to the same body by different workers. It is tolerably 
certain that three bases at least are present — ergotinin, C35H39O5N5, the 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 301 

hydrate of which, ergotoxin, C35H41O6N5, has a powerful physiological 
action; tyramin or hydroxyphenylethylamin, OH • C6H4 • CH2CH • NH2, an 
important heart stimulant; and isoamylamin, (CHs^CHCHfeCB^NKfe. 
The drug also contains a coloring substance which is of great assistance 
to the analytical chemist for purposes of identification. Ergot contains 
about 30 per cent of fixed oil and fat. 

Ergotinin, C35H39O6N6 

Ergotinin crystallizes in long needles which, when subjected to the 
temperature of a bath at 210° and further heated, sinter, darken, and melt 
up to 229°. It is soluble in alcohol, acetone, ethyl acetate, and chloro- 
form; moderately soluble in ether, benzole, and amyl alcohol, and nearly 
insoluble in petroieum ether. When boiled in dilute phosphoric acid 
ergotoxin phosphate is formed. 

Ergotinin is removed from alkaline solutions by ether. A solution of 
this alkaloid in sulphuric acid gives with ferric chloride an orange-red 
color, becoming deep red, with a blue to bluish green margin. A solu- 
tion in glacial acetic acid, to which ferric chloride is added and cautiously 
treated with sulphuric acid, will yield a violet zone at the point of contact. 

Ergotinin is probably the cornutin of some investigators. 

Ergotoxin, Hydro-Ergotinin, C35H41O6N5 

Ergotoxin is a light white powder, which begins to soften at 155° and 
melts gradually at 162-164°. It is more soluble in organic solvents than 
ergotinin, though only slightly in ether, and more sensitive towards alka- 
loidal reagents. When boiled with acetic anhydride a molecule of water 
is split off and ergotinin results. Solutions of both ergotinin and ergo- 
toxin are fluorescent. 

Para-hydroxyphenylethylamin. Tyramin, OH • C 6 H 4 • CH 2 CH 2 NHj 

This base can be extracted from ergot extracts only with great dif- 
ficulty on account of its ready solubility in water. It may be removed 
by amyl alcohol from a concentrated solution made alkaline with sodium 
carbonate. When crystallized from alcohol it forms hexagonal leaflets, 
melting 161 \ It is soluble in 10 parts of boiling alcohol, somewhat less 
soluble in boiling water, and still less in boiling xylol. 

When treated with methyl iodide, a quaternary iodide is obtained 
which is identical with the methiodide of hordenin. 

Barger and Dale isolated an active principle from ergot, the relative 
abundance of which suggested that it was wholly or partly produced by 
micro-organisms. They isolated the base by means of Kutscher's 1 
1 Z. Unters. Nahr. Genussm., 1905, 10, 528; 1906, 11, 582. 



302 ALKALOIDAL DRUGS 

method and obtained the silver compound. The hydrochloride, picrate 
melting 220-230°, and picrolonate melting 250° were prepared, and the 
base gave Pauly's reaction with p-diazobenzenesulphonic acid. The 
investigators consider that the new base is /3-iminazolylethylamin. 

Ergot contains an undetermined substance which has been called 
ergoxanthein or ergot-yellow by Wengell, and which is of importance in 
identifying the drug. It may be separated by treating an evaporated 
alcoholic extract of the preparation with water, filtering, washing the 
undissolved material with water, and extracting the filtrate first with 
chloroform and then with ether, the latter removing the ergoxanthein. 
It is an orange-yellow substance soluble in alcohol, ether, benzol, ethyl 
acetate, amyl alcohol, acetone, and carbon bisulphide. A residue of the 
separated substance is practically insoluble in water and chloroform. It 
gives a dark-orange color with concentrated nitric acid. It is precipi- 
tated from alcoholic solution by basic lead acetate and phosphotungstic 
acid, but not by barium chloride. Its alcoholic solution becomes blood 
red when rendered strongly ammoniacal and gives a characteristic absorp- 
tion spectrum. 

This test is probably the same as tnat described by Schmidt, who 
designates as sclererythrin a pigment existing in the outer coat of the ergot. 
It is an amorphous red powder, subiimable, soluble in alcohol and glacial 
acetic acid, slightly in ether, and insoluble in water and petroleum ether. 
It dissolves in ammonia, alkali hydroxides, carbonates, and bicarbonates 
with a red or red-violet color. An ethereal solution colors sodium hydrox- 
ide a deep red and the colored solution shows characteristic absorption 
bands. Sclererythrin gives blue-violet precipitates with solutions of cal- 
cium hydroxide, barium hydroxide, and lead acetate. Iron chloride pro- 
duces a deep-green precipitate, and chlorine or bromine a lemon-yellow. 

In working with mixtures an evaporated alcoholic extract of the 
sample is treated with tartaric acid and digested with alcohol, the alcohol 
filtered, evaporated, and the residue treated with ether. The ether is 
filtered into a separator and shaken with 1 to 2 c.c. of cold saturated sodium 
bicarbonate solution, which becomes violet if sclererythrin is present. 
If the ether solution be shaken with ammonia, the alkaline liquid sepa- 
rated and precipitated with basic lead acetate, the precipitate will color 
a cold saturated borax solution a red-violet color. 

ALKALOIDS OF THE CALABAR BEAN 

Physostigmin, C15H21N3O2. 
Physovenin, C14H18N2O3. 
Eseramin. 
The drug yielding the above mentioned alkaloids is the ripe seed of 
Physostigma venenosum (Fabacese), commonly known as Calabar Bean. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 303 

The plant is a tall creeper and the seed is contained in long pods, two or 
three kernels occurring in each. The fallen seeds are collected by the 
natives and used by the medicine men in their ordeal tests, from which 
these seeds have derived the name of " ordeal bean." 

The drug is official in the several pharmacopoeias, but it is probable 
that the seeds from other species of Physostigma are sometimes substi- 
tuted for P. venenosum in the preparation of medicinal products. 

The drug is rarely used in medicine, but physostigmin salicylate and 
sulphate are employed in tablet form and usually unaccompanied by other 
agents. An extract of the drug is sometimes combined with belladonna, 
colocynth, and Podophyllum. Physostigmin is dispensed with pilocarpin 
and is often used in veterinary practice for colic in horses. The alkaloid 
may be anticipated in remedies used in traumatic tetanus, strychnin 
poisoning, muscular rheumatism, spinal menengitis, torpid constipation, 
and chronic bronchitis. It is a powerful myotic. 

Physostigmin 

Physostigmin, also known as eserin, crystallizes from a mixture of 
benzol and petroleum ether in prisms melting 86-87°. It is dimorphous, 
the modification melting 105-106°. Both modifications are lsevorotatory 
to the same degree (<x)d- 75.8°. Physostigmin is slightly soluble in water 
and petroleum ether and dissolves readily in the other organic solvents. 
It yields precipitates with most of the common alkaloidal precipitants, but 
with platinic chloride, mercuric chloride and potassium chromate precipi- 
tation occurs only when the solution is concentrated, and potassium iodide 
and ferrocyanide give no precipitate. A purplish-brown precipitate is 
thrown down with gold chloride and the solution turns brown, becoming 
red in ten to fifteen minutes. The platinum compound melts at 180° C. 
with decomposition, the gold salt at 163-165°. 

When a solution of physostigmin is treated with a slight excess of 
ammonia, alkali or alkali carbonate, a pink color develops at once, due 
to oxidation and formation of rubreserin. If a solution is oxidized in 
the presence of potassium hydroxide and oxygen and then just neutralized 
with sulphuric acid, the rubreserin can be extracted with chloroform and 
left as a deep red substance on evaporating. Its formula is 

CiaHieCySfe-HgO. 

Another interesting oxidation product is eserin blue, which is formed 
when an alcoholic solution of physostigmin is treated in a flask with an 
aqueous solution of barium hydroxide and about one-quarter the volume 
of air. The red color first obtained soon changes to green and then to 
blue when more air is admitted, and the addition of air may be repeated 
until a deep blue solution is obtained. The oxidation product is soluble 



304 ALKALOIDAL DRUGS 

in chloroform and may be extracted from the latter with dilute hydro- 
chloric acid. 

Physostigmin gives a yellow color with concentrated sulphuric acid, 
soon turning orange; on adding potassium iodate a purple tint is pro- 
duced changing to yellowish red; with nitric acid a blood-red residue 
turning green is obtained on evaporation, and the subsequent addition 
of alcoholic potash produces a brownish-green solution, with a momentary 
purple shade in thin layer, the solution becoming green on the subsequent 
addition of acetic acid; Froehde's reagent gives a violet color, turning 
brown. Hot ammonia added to a physostigmin residue produces a yellow- 
ish-red solution, on evaporation a blue or blue-green residue is left, 
soluble in alcohol to a blue solution which becomes violet-red and fluores- 
cent on adding acetic acid. 

Physostigmin forms well-defined salts of which the sulphate, salicylate, 
benzoate, and hydrobromide are best known. The salicylate is soluble 
1-70 or thereabout in water and may be obtained as a precipitate by 
adding sodium salicylate to a concentrated neutral solution of the sul- 
phate. The picrate melts 133° C. 

The composition of physostigmin has been studied by Salway, 1 but 
the work is not completed. By alkaline hydrolysis eserolin is obtained 
according to the equation 

(Ci 3 Hi 6 ON)NH ■ CO NH ■ CH3+ H 2 = Ci 3 Hi 6 ON Nlfe-i-CCb + NH2CH3. 

Eserolin is a strong base, probably an indole derivative. 

Physovenin 

This is a weak base discovered by Salway 2 in his researches on the 
Calabar bean. It is moderately soluble in ether and readily in alcohol, 
benzol, and chloroform. It dissolves in strong mineral acids but is again 
precipitated on dilution. It precipitates barium carbonate from a solu- 
tion of barium hydroxide, and the solution becomes red. Salway believes 
that physovenin is an intermediate product in the conversion of physos- 
tigmin into eserolin. It is a powerful myotic. 

Previous investigators have reported the presence of bases called 
isophysostigmin and eseridin in Calabar beans, but Salway was unable 
to find any substances answering their description. 

Eseramin 

This alkaloid, which was found by Salway in very small amount in 
the Calabar bean, is sparingly soluble in ether, chloroform, and benzol 

1 Trans. Chem. Soc, 1912, Vol. 101; 1913, Vol. 103. 

2 Ibid., 1911, Vol. 99. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 305 

and readily in alcohol. It is apparently left behind in an ethereal solu- 
tion on shaking with weak acid, but dissolves in strong mineral acids and 
gives a precipitate with Mayer's reagent. 

Geneserin 

A base to which this name has been given and having the formula 
C15H21O3N3, was reported by Polonovski. 1 He obtained it by extracting 
the beans with ether in the presence of sodium bicarbonate. The ethereal 
solution was shaken out with sulphuric acid, the alkaloids liberated with 
bicarbonate, extracted with ether and the solvent evaporated. The resi- 
due was oily and on standing the geneserin crystallized. From the resi- 
dual oil the physostigmin was separated by the addition of salicylic acid. 

The identification of physostigmin in medicinal products presents little 
difficulty. In the customary scheme of analysis it will be obtained on 
shaking out an alkaline solution with ether and its presence will have been 
suspected by the pink color which appears when the acid solution is made 
ammoniacal. The residue should be separated into several fractions and 
the different color tests applied. If desired a physiological test may be 
conducted by applying a solution of the base to the eye of some animal 
having a large pupil. 

A quantitative determination is best made by crushing a number of 
tablets, and introducing the powder into a separator, moistening with 
water, rendering slightly acid and then adding a slight excess of sodium 
bicarbonate. The physostigmin can then be extracted by shaking ten 
times with small quantities of ether, the solvent combined, washed with 
water, filtered into a tared dish, evaporated and the residue weighed. 

ALKALOIDS OF PAREIRA ROOT 

The root of Chondrodendron tomentosum (Menispermaceae) yields the 
drug Pareira Brava. The plant is a perennial climber, native of Brazil and 
Peru. The drug is often substituted by, and sophisticated with other 
roots, some of which include C. platyphyllum, Stephania discolor, white 
pareira from Alrita rufescens, yellow pareira from A. amara, and false 
pareira from Cissampelops Pareira. 

The extract of the drug is used as a tonic, aperient, and diuretic, and 
may be suspected in medicines recommended for affections of the kidneys, 
leucorrhea, dropsy, rheumatism and jaundice. 

The alkaloid bebeerin, CieHisOfOHMOCI^NCHs, has been identi- 
fied among the bases of Pareira barva, and has been studied to some 
extent by Scholtz, 2 who finds that it exists in two forms, one of which 
is crystalline, melting 214°, when obtained from methyl alcohol, and the 
other amorphous, when obtained from other solvents. Scholtz found 
1 Bull. Soc. Chem.. 17. 235. 2 Arch. Pharm., 244, 555. 



306 



ALKALOIDAL DRUGS 



that on extracting the drug with dilute sulphuric acid and adding sodium 
hydroxide, he obtained a brown resinous mass yielding about 10 per cent 
of amorphous bebeerin when extracted with ether. By extracting the 
remaining insoluble mass with pyridin and precipitating with methyl alco- 
hol he obtained a nearly white powder of the same composition and nearly 
the same properties as bebeerin, but differing from it in being less soluble 
and melting at 300°. A crystalline alkaloid which he had previously 
isolated had an optical rotation of —298°, while the base extracted above 
gave a rotation of +297°. In other respects they were identical, both 
melting 214°. When concentrated chloroform solutions of these two 
bases were mixed they soon became turbid and a precipitate settled out 
which, on drying, was found to melt at 300°. The two active forms are 
soluble in acetone and chloroform while the product of the ether mixture 
noted above is practically insoluble. Scholtz concludes that the new com- 
pound is the racemic form of the alkaloid, and that sometimes one and 
sometimes the other form of the alkaloid may predominate in the plant. 
The active forms do not change to the racemic form by the action of sol- 
vents or the chemicals used in the separation of the alkaloids from the drug. 

The alkaloidal residue from Pareira gives a purple color with con- 
centrated nitric acid. 

Scholtz - 1 also obtained from Pareira a base which he calls chondrodin. 
It is soluble in dilute acids and alkalies, but not in the ordinary organic 
solvents except alcohol and aniline. Like bebeerin it is very easily oxi- 
dized, but it differs from bebeerin in giving no characteristic color tests. 

The composition of the greater portion of the basic residue obtained 
from Pareira is as yet undetermined owing to its tendency to resinify. 
The bases thus far isolated oxidize with ease, and it is probable that their 
transformation products make up the larger portion of the alkaloidal 
content of the drug. Commercial bebeerin sulphate probably consists 
in large part of these transformation products. 

Faltis 2 has worked with commercial bebeerin sulphate, and from it 
claims to have extracted several alkaloids more or less similar to the 
bebeerin of Scholtz. 

CACTUS ALKALOIDS 

Anhalin, C10H17NO. 
Mescalin, CyHsCOCEWaN-CHa. 
^ — Anhalonidin, C12H15NO3. 
^- Anhalonin, C12H15NO3. 
Lophophorin, C13H17NO3. 
Pellotin, Ci HioO(OCH 3 )2N-CH3. 
Anhalamin, C11H15NO3. 
1 Arch. Pharm., 249, 408. 2 Monats. Chem., 1912, 33, 873. 



ALKALOIDS WITH NO PYRIDIN NUCLEUS 307 

These bases occur in several species of Lophophora and Anhalonium 
(Cactacese) growing chiefly in Mexico. The dried tops of L. williamsii 
and L. lewinii constitute the drug, and are more or less button-shaped, 
accounting for the name mescale button, the term commonly used in 
designating the product. The drug is a powerful sedative and cardiac 
tonic. It is seldom used in this country and at the present time the 
. importation is forbidden. 

Lophophora lewinii contains mescalin, anhalonidin, anhalonin, lopho- 
phorin, anhalamin, and possibly pellotin. 

L. williamsii contains pellotin and probably the other bases mentioned. 

Anhalonium fissuratum contains anhalin. 

Anhalin 

Anhalin forms stellate masses of white prisms, melting 115°, slightly 
soluble in cold water, more so in hot water, and very easily in alcohol, 
methyl alcohol, ether, chloroform and petroleum ether. When dissolved 
in concentrated sulphuric acid and treated with a drop of nitric, a green 
color is produced. 

Mescalin, CH3 NHCH 2 C6H 2 (OCH 3 ) 3 (l : 3 : 4 : 5) 

Mescalin crystallizes in small white needles, melting at 151°, readily 
soluble in water, benzol, chloroform, and alcohol, but only slightly in 
ether and petroleum ether. It gives precipitates with the usual alkaloidal 
reagents. 

Mescalin was reported by Heffter 1 to form small white needles soften- 
ing at 105° and melting 150-160°, but later he found that it was an oily 
liquid which absorbed carbon dioxide, forming a crystalline carbonate. 

The base is soluble in water with a strong alkaline reaction ; the aqueous 
solution expels ammonia from its salts and precipitates the hydroxides 
from copper, lead, and zinc salts. 

The alkaloid produces intoxication, the user experiencing remarkable 
color visions. 

Anhalonidin, (CH 3 O) 2 (OH)C 10 H 7 : NH 

Anhalonidin crystallizes in small yellow needles, melting 160°, and is 
readily soluble in water and the usual organic solvents. When recrys- 
tallized from benzol it forms small octahedra which soften at 151° and 
melt at 154° with discoloration. Its aqueous, solution is alkaline. It is 
precipitated by alkaloidal reagents. 

Solutions of its salts give a blue color with ferric chloride, turning 
green on warming and then disappearing. 

1 Ber., 1901, 34 (12) 3004. 



308 ALKALOIDAL DRUGS 



Anhalonin 

Anhalonin melts 85.5° and boils without decomposition. It is much 
less soluble in water than either mescalin or anhalonidin. 

Lophophorin 

Lophophorin separates in the form of oily drops on adding alkali to 
a solution of its salt. It does not crystallize. 

Mescalin, anhalonidin, anhalonin, and lophophorin yield the same 
color reactions with sulphuric acid both alone and in presence of nitric; 
sulphuric gives a yellow solution, changing to violet on the application 
of heat; on adding nitric a deep violet changing to brown is obtained. 

Pellotin, C 10 HioO (OCH 3 ) 2 N ■ CH 3 

Pellotin forms hard, colorless, tabular crystals, melting 110°, slightly 
soluble in cold water, readily in alcohol, acetone, ether, and chloroform. 
When dissolved in concentrated sulphuric acid and treated with a drop 
of nitric, an intense permanganate color develops. 

Solutions of its salts give a blue color with ferric chloride, turning 
green on warming and then disappearing. 

Anhalamin, C9H 7 (OCH s ) 2 (OH) : NH 

Anhalamin crystallizes from absolute alcohol in spherical aggregates 
of microscopic needles melting at 185.5°. It is soluble in hot water, from 
which it crystallizes in needles. 

Aqueous solutions of its salts give a blue color with ferric chloride, 
which turns green on heating and then disappears. Pellotin and anha- 
lonidin give the same reaction, but not mescalin, anhalonin, and lopho- 
phorin, which contain no hydroxyl group. 






Part III 

GLUCOSIDES, GLUCOSIDAL DRUGS AND 
NATURAL DRUGS CONTAINING PRIN- 
CIPLES OTHER THAN ALKALOIDS 



CHAPTER X 
GLUCOSIDES 

Definition 

The chemistry of the glucosides is in a far less advanced state than 
that of the alkaloids. Many substances which were formerly looked 
upon as glucosides have been carefully studied and found to be mixtures 
of several bodies often of no glucosidal character. We are indebted to 
Dr. Power (late of the Wellcome Research Laboratories) and his associ- 
ates for clearing up many points in this field. The work of these men in 
determining the actual chemical composition of drugs has been a great 
step in the advancement of medicinal chemistry, and as a result of their 
researches the list of individual glucosides has been considerably cur- 
tailed. Formerly it was customary to consider that if a plant did not 
contain an alkaloid or some acidic or readily recognizable ingredient, it 
probably contained a glucoside. And if it contained a little resin, which 
most plants do, this resin was given some name significant of the plant 
and called a glucoside. But these vague resins have now been subjected to 
systematic analysis and their true character determined; thus " Jalapin " 
and " Convolvulin," which for years held a prominent place in the chem- 
istry of jalap, have been relegated to the mythology of our science, and 
many others, " leptandrin," " euonymin," " caulophyllin," " taraxacum" 
for example, have become tradition. 

The term glucoside is applied to a substance belonging to a class of 
organic compounds which under proper conditions may be resolved into 
two stable, simpler bodies, one of which is always a sugar and the other 
of phenolic, acidic, alcoholic, or neutral nature. This resolution is in 

309 



310 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

the nature of an hydrolysis, the elements of water being divided between 
the new bodies. Glucosides are usually of high molecular weight and 
are composed of carbon, hydrogen, and oxygen, with sulphur or nitrogen 
in rare instances. They are found widely distributed in nature and can 
be prepared synthetically. 

The resolution of the glucosides may be brought about by enzymes 
existing in the plant, and often by the time a drug is incorporated in a 
medicinal product the hydrolysis will be completed. It may also be accom- 
plished by boiling the glucoside with water, and is readily effected by the 
action of hot dilute mineral acids. 

The study of glucosides is concerned more with a consideration of 
their products of hydrolysis than with the substances themselves, because 
the resolution products usually can be handled and submitted to various 
reactions without further decomposition, while the glucosides may be in 
process of breaking up during the analysis, and the reactions will be com- 
plicated by the presence of the resolution products. 

Glucosides are relatively indifferent substances; they do not yield salts 
like the alkaloids, and they are not removed from immiscible solvents by 
either acid or alkali. They are usually soluble in alcohol and water, 
and if soluble in any immiscible solvent, such as ether or chloroform, 
they may be removed from their aqueous solution slowly but more or less 
completely by these agents. As a rule the glucosides are much less soluble 
in ether and chloroform than in water and alcohol, and in some instances 
they are practically insoluble, or so little soluble that they are not removed 
fi'om aqueous solution. On the other hand, while of course the sugar is 
usually very soluble, the other resolution product is usually much less 
soluble in water than the original glucoside and much more soluble in 
immiscible solvents, so that after hydrolysis it is separable from the acid 
liquid. Furthermore this resolution product often reacts with an alkali 
and hence may be shaken out from its solution in an immiscible solvent. 

The reactions of glucosides with precipitating and color producing 
reagents are much less characteristic than is the case with alkaloids. 
They do not react with potassium mercuric iodide, and hence, in a mix- 
ture, the alkaloids can be separated without difficulty. A few of them 
are precipitated by tannic acid, picric acid, lead acetate and basic lead 
acetate, and a solution of ammonium molybdate slightly acid with hydro- 
chloric acid. Some of them give fairly characteristic colors with sul- 
phuric or nitric acid, but the tests that are reported have been made with 
impure products so often, that the chemistry in this respect is confusing. 

The majority of glucosides yield ordinary dextro-glucose on hydrolysis, 
some rhammose, some galactose, and a few give sugars whose nature 
appears to be somewhat extraordinary and in some cases needs further 
Study. 



GLUCOSIDES 311 

Some of the glucosides are extremely poisonous. Some give solutions 
which froth on agitation. 

The chemistry of glucosidal drugs is intimately associated with that 
of the resins, and with our present knowledge of the subject it is impossible 
to draw a distinction between drugs whose activity depends solely on 
their resinous constituents, those whose activity depends on both resin- 
ous and glucosidal constituents, and those whose activity depends on 
glucosides alone. Again, it is probable that in many cases the activity 
is independent of any of these components. In this section we shall 
endeavor to classify the drugs according to their most prominent ingredi- 
ent, and in general it will be noted that in each class the uses to which 
the drugs are put will be of a similar nature. 

Heart Tonic Drugs and Their Glucosides — Strophanthus, Digi- 
talis, CONVALLARIA, SQUILL 

THE STROPHANTHUS GLUCOSIDES 

There are thirty or more species of Strophanthus, and the seeds of 
S. Kombe and S. hispidus are official. The seeds of other species are sold 
on the market and probably are often mixed with the official drug. Their 
active principles are glucosidal substances of an extremely poisonous 
nature. 

On account of the extreme toxicity of this drug and of the pure 
strophanthin, which is also an article of commerce, they will be encountered 
but rarely in analytical work except in products where their presence is 
already declared. 

Strophanthus is a powerful cardiac stimulant and has diuretic proper- 
ties. The true strophanthin glucoside is a cardiac stimulant, but is 
reported to be without diuretic action. The drug is dispensed in the 
form of a tincture, the extract is made up into pills and tablets, and stro- 
phanthin is administered in tablet form. Most of the mixtures of Stro- 
phanthus or its glucosides with other drugs are intended for heart tonics, 
and these combinations usually contain cardiac drugs. Thus we meet 
with combinations of Strophanthus with Cactus grandiflorus, spartein, 
strychnin, nitroglycerin, and Digitalis glucosides; with spartein, codein, 
and caffein; with caffein, nitroglycerin, and Digitalis; with nitroglycerin 
and Digitalis; and to some of these combinations reduced iron or Blaud's 
mass may be added. 

The seeds of S. Kombe contain from 2 to 3 per cent of strophanthin, 
a large amount of fixed oil, kombic acid, choline, trigonelline and other of 
the more common plant constituents. 

The latex of S. glaber syn. gratus contains ouabain, which is also known 



312 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

as G-Strophanthin. It is closely related to strophanthin, the latter being 
apparently its methyl derivative. 

Pure strophanthin, C40H56O15+3H2O, crystallizes in fine white needles 
or long plates. Its water of crystallization may be expelled by heating 
in vacuo to 80°, and the anhydrous substance melts 178-179°. The 
anhydrous glucoside is hygroscopic and the crystalline form melts in its 
water of crystallization at about 158°. Strophanthin is readily soluble 
in alcohol and the solvent on evaporation leaves a resinous mass. It is 
soluble in water, but is not dissolved by ether, carbon bisulphide, or petro- 
leum ether, and only slightly by chloroform and benzol. Alcohol and 
chloroform mixtures remove strophanthin gradually from an aqueous solu- 
tion, especially if saturated with sodium chloride. 

With concentrated sulphuric acid it turns dark green and then brownish. 
When warmed with sulphuric acid the green color changes to violet shades 
and finally blackish. Sulphuric acid containing phenol gives a violet 
color, soon becoming green. An aqueous solution froths on shaking, and 
gives a precipitate with tannic acid, which dissolves in an excess of the 
reagent. No precipitate is produced by lead acetate, basic acetate, iodin, 
or Mayer's reagent. Dilute nitric acid dissolves strophanthin without 
color, but on heating to 50° a violet color appears changing to yellowish. 
Liquid preparations of Strophanthus seeds will give a precipitate with 
lead acetate due to the presence of kombic acid. 

When strophanthin is warmed with 1 per cent hydrochloric acid to 
70-75° it is split up into strophanthidin and a reducing sugar, the former 
separating out on cooling. It may be recrystallized out of hot alcohol and 
contains one molecule of water of crystallization, C27H38O7+H2O, It 
fuses at about 120° in its water of crystallization to a turbid mass and is 
liquid at about 170°. When dried it melts 169-170°, foaming at 180° 
and on cooling solidifies to a mass which melts at 232°. Its specific rota- 
tion is +44.2 to +44.3. Strophanthidin may be removed from an acid 
solution by shaking out with chloroform. As far as has been determined 
it has the characteristics of a dilactone. 

The character of the sugar has not been definitely settled. Some 
investigators claim that it is rhamnose, but others believe it to be a com- 
plex carbohydrate which on further treatment gives rhamnose, mannose 
and methyl alcohol. 

Brauns and Closson 1 as the result of an extended research on the 
glucosides of Strophanthus conclude that the seeds of S. Kombe contain 
two glucosides, the crystalline strophanthin above described, and a closely 
related amorphous strophanthin of apparently twice the molecular weight. 
By the action of water on the crystalline strophanthin there is formed a 
monobasic acid strophanthin or a mixture of a monobasic acid, a dibasic 
1 Journal Am. Pharm. Ass., 1913, 489. 



GLUCOSIDES 313 

acid, and the original crystalline strophanthin. These three strophan- 
thins, the crystalline, acid, and amorphous, all give the same strophan- 
thidin on hydrolysis. Crystalline strophanthin contains neither a pentose 
nor a methyl pentose (rhamnose), but amorphous strophanthin contains 
a pentose. The hydrolysis of the crystalline substance apparently takes 
place according to the following reaction: 

C40H06O15+4H2O = C27H38O7+C12H22O11+CH3OH 

strophanthidin disacchaiide 

Other workers have shown that authentic seeds of S. hispidus do not 
contain a crystalline glucoside, but an amorphous body which is identical 
or closely related to the amorphous strophanthin mentioned above. Both 
the crystalline and amorphous acid strophanthin show the typical heart 
tonic response, diminished rate, and increased amplitude of the heart 
beat, accompanied by a small rise in blood pressure, but the activity of 
the amorphous acid strophanthin is less than that of the crystalline. 

Ouabain, the crystalline glucoside from S. gratus, is about twice as 
toxic as crystalline Kombe strophanthin. 

The seeds of Strophanthus hispidus have been investigated by Heffter 
and Sacks, 1 who reported the presence of an amorphous glucoside giving 
a green color with sulphuric acid and a crystalline strophanthidin. 

Sieburg 2 states that the hemolytic saponin, strophanthic acid, which 
Kobert has previously reported as being an accidental impurity of com- 
mercial strophanthin, is contained in varying proportions up to 0.2 per 
cent in all varieties of the drug, from the alcoholic solution of which it 
may be obtained by precipitation with an acid after removal of the alcohol. 
The pure saponin, (C2iH3.iOio)4, is of acid nature, is precipitated from its 
solutions in water or alkali by picric or phosphomolybdic acid and also 
by concentrated ammonium sulphate and sodium chloride. It is readily 
soluble in aqueous alcohol, but sparingly in water. With salts of some of 
the heavy metals it forms precipitates of indefinite composition. On 
hydrolysis with acids it is resolved finally into dextrose and strophan- 
thigenin, (Ci2His02)23H20, a sapogenol which likewise possesses hemo- 
lytic properties. 

Rezzaghi 3 describes a number of color reactions which are given by 
strophanthin and which can be used for testing the tinctures and liquid 
preparations. The alcohol is evaporated, the residue diluted with water 
to 20 mils and divided into four parts. To (1) 2 mils pure concentrated 
sulphuric acid containing a trace of iron perchlorate are added, when a 
rose-brown precipitate is thrown down, which soon changes to green- 
brown. To (2) the tannin reaction is applied. To (3) a few drops of 

1 Biochem. Zeits., 40 (1912), 83. 2 Ber. deuts. Pharm. Ges., 1913, 23, 278. 

3 Bol. Chim. farm., 51-5, 149. 



314 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

silver nitrate are added and on warming a deposit of metal is obtained. 
To (4) 2 drops of dilute sulphuric acid and a few drops of bichromate 
are added which produce an azure blue color. 

Ouabain 

Ouabain, G-Strophanthin, C30H46O12+9H2O, is obtained from ouabaio 
wood or from Strophanthus gratus. 

It forms colorless quadratic crystals of bitter taste, easily soluble in 
hot water, soluble in 100 parts of cold water and 30 parts cold absolute 
alcohol and 30 parts amyl alcohol. It is slightly soluble in acetic ether, 
ether, and chloroform. 

A solution of 0.01 gram in 1 mil water run onto a layer of concentrated 
sulphuric acid colors the latter pink to red, and the aqueous layer is colored 
a dirty-green color. 

Heated to 105° C. it loses 20 per cent of water and the ouabain thus 
dried melts at 187° to 188° C. 

Heating with dilute hydrochloric acid or sulphuric acid produces 
hydrolytic cleavage, but the strophanthidin-like substance is amorphous. 

Crystallized ouabain is used in place of Strophanthus or strophanthin 
as a substitute for Digit alis. 

Antiarin 

Antiarin is a glucoside occurring in the latex of Antiaris toxicaria of 
Java. There are apparently two forms which have been described as 
alpha and beta, and their action closely resembles that of the Digitalis 
glucosides. They are not used medicinally. 

In the general scheme of analysis using immiscible solvents, strophan- 
thin will not be removed until the alkaline solution is agitated with the 
chloroform-alcohol mixture, when it will be extracted in part, and more 
readily if the solution is saturated with salt. 

The presence in a mixture of an heart-stimulating principle is most 
conclusively ascertained by subjecting the same to a physiological test. 
For details of work of this character one must refer to works on pharma- 
cology. Even though the presence of an heart stimulant is indicated by 
physiological test the identity of the principle will require substantiation 
by chemical means, and as strophanthin yields strophanthidin so readily 
on acid hydrolysis, a procedure with this end in view should be adopted 
and the decomposition product shaken out with chloroform and recrys- 
tallized. 

In quantitative work the hydrolysis to strophanthidin and its recovery 
with chloroform along the lines indicated in Haycock's assay process for 
the seeds, can be employed to advantage. In mixtures containing alka- 
loids, an alcoholic extract should be evaporated and then taken up with 



GLUCOSIDES 315 

water or very weak acid, which is immediately made alkaline and the 
alkaloids shaken out with ether and chloroform. The alkaline solution 
is then neutralized with hydrochloric acid and an excess added up to 1 
per cent, heated to 70-75° for half an hour, subsequently shaking out with 
chloroform to remove the strophanthidin, which can then be recovered 
and weighed. 

THE DIGITALIS GLUCOSIDES 

The leaves and seeds of several of the Digitalis species contain a num- 
ber of glucosides, some of which possess marked physiological activity, 
affecting the heart and blood. The leaves of D. purpurea, purple fox- 
glove, are designated as the official drug, and the seeds are used for the 
preparation of the commercial glucosides. 

The chemistry of the plant is very imperfectly understood, several 
principles have been isolated in a greater or less degree of purity, but 
unfortunately there is a confusion of nomenclature and the same name 
may be applied in a commercial way to several mixtures of entirely dif- 
ferent appearance and action. This is especially true of the term " digi- 
talin," which is not only applied in a scientific way to one of the gluco- 
sides, but also to commercial mixtures of the glucosides. Thus we have : 

Digitalinum purum, or German digitalin, a mixture of several gluco- 
sides, consisting of 50 to 60 per cent of digitonin and only 5 to 6 per cent 
of true digitalin. German digitalin is the preparation usually found on 
the market and is ordinarily dispensed when " digitalin " is prescribed. 

French digitalin, or Homolle's digitalin, a mixture of several gluco- 
sides, but consisting mainly of true digitalin. 

Merck's crystallized digitalin is neither digitalin nor digitoxin, but 
digitonin or digitin, Merck using the three terms, crystallized digitalin, 
digitonin, and digitin as synonyms. 

Digitaline crystallisee of Nativelle is not -digitalin, but is nearly iden- 
tical with digitoxin. 

Digitalis functionates in medicinal preparations in several forms; first 
as an extract of the drug prepared by simple extraction with solvents, 
second as a partially purified and perhaps concentrated extract which is 
sold under various trade names, and third as a purified or perhaps it 
would be more correct to say a partially purified mixture of its active 
principles, chiefly glucosides. 

While its chief use is as a heart tonic, Digitalis is also found in diuretic 
mixtures, and seems to be particularly useful in dropsy and in renal ob- 
struction. 

Where the drug is dispensed in the form of its fluid, solid or powdered 
extract or concentration it will be found alone in pills and tablets of definite 



316 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

strengths, and combined with caffein; with Squill and potassium nitrate 
or mercury, sometimes with the addition of buchu, juniper, or other mild 
diuretic; with phosphorus and Hyoscyamus; with phosphorus and iron; 
with phosphorus, ipecac, and opium with perhaps iron and quinin; with 
Cannabis sativa and iron; with nitroglycerin; with Strophanthus; with 
aconite; with strychnin and belladonna and sometimes in different com- 
binations with the five last named; with ergot and quinin; with Cactus 
grandiflorus, spartein, Strophanthus and strychnin; with gold and sodium 
chloride, strychnin, atropin, nitroglycerin, and Capsicum; with sodium 
bromide, acetanilid, and hyoscyamin, with sodium salicylate and col- 
chicin; with iodides, guaiac, colchicin and Phytolacca decandra; and other 
preparations of the same general composition. 

In the form of a concentrated and partially purified extract it is gener- 
ally dispensed by itself and as stated above a preparation of this type will 
have a name suggestive of the drug, as for instance " Digitaline," "Diga- 
tol," " Digitone," " Digitalen," etc. 

The separated glucosides, which in the commercial form generally go 
by the name " digitalin," are dispensed in tablet triturates and hypodermic 
tablets of different strength. Digitalin is also combined with nitroglycerin, 
strychnin, and strophanthin. 

The drug may be found adulterated with the leaves of mullein (Ver- 
bascum thapsus), primrose, comfrey (Symphytum officinalis), and matico 
(Piper angustifolium). 

The chemical examination of Digitalis has resulted in the isolation of 
several glucosides, and while some are of doubtful identity, it seems prob- 
able that those having some claim to individuality are digitoxin, digitalin, 
digitonin, digitalin, and perhaps digitalein. Recently Windaus and 
Schneckenberger x have reported a new glucoside which they have extracted 
from German " digitalin " and to which they give the name gitonin. 

Berry 2 has conducted a phytochemical research on the leaf which may 
be summarized as follows: 

He found digitoxin, 0.1-0.3 per cent, insoluble in water, but soluble 
in diluted alcohol; digitalein or gitalin, 0.3-0.9 per cent, a glucoside soluble 
in water; two saponins, 0.6 per cent, (a) digitonin, amorphous, soluble 
in water, (6) gitin, crystalline, insoluble in water; a fat or resin extracted 
by ether, which acts as an irritant; a fluorescent body, luteolin or digi- 
toflavone; an active enzyme or oxydase. 

Digitoxin, C34H54OU 

Depending on the solvent from which it is crystallized, it is either 
hydrated or anhydrous. The hydrated form is obtained when crystallized 

1 Ber., 1913, 46, 2628. 2 Pharm. J., 1915, 95, 783. 



GLUCOSIDES 317 

from alcohol and the anhydrous from chloroform and alcohol mixture, 
forming colorless rectangular leaflets melting at 243° C. 

It is insoluble in water, benzin, or carbon disulphide, slightly soluble 
in ether, and easily soluble in chloroform. At 15° G it is soluble in 79.80 
parts of absolute alcohol and in 43.04 parts of 90 per cent alcohol. It 
is slightly soluble in fatty oils. 

Digit oxin dissolved in 2 mils glacial acetic acid containing a trace of 
ferric chloride when poured onto 2 mils of concentrated sulphuric acid 
containing a trace of ferric chloride, will produce a brown color at the 
zone of contact of the two solutions. This color gradually changes to 
green and finally an indigo blue; after one-half hour tha entire acetic 
acid layer will become blue. 

It dissolves to a colorless solution in cold concentrated hydrochloric 
acid, but when this solution is heated on the water-bath for some time a 
green color is obtained. Concentrated sulphuric acid dissolves it, pro- 
ducing a green color. 

Digitoxin on hydrolysis with 50 per cent alcohol containing 1 per cent 
of concentrated hydrochloric acid, yields digitoxigenin, C22H32O4, melting 
230°, and digitoxose, C6H12O4, the latter decomposing readily by boiling 
with dilute hydrochloric acid. It differs from Z-arabinose and does not 
give furfurol on distillation with hydrochloric acid. 

Digitoxin may be obtained from the drug as follows: 

The leaves having been extracted with water, and dried, are extracted 
with 50 per cent alcohol. This solution is treated with lead acetate, form- 
ing a precipitate which is allowed to settle. The supernatant liquid is 
decanted. The remaining alcohol is evaporated in vacuo and the residue 
repeatedly extracted with ether. The ether extract is then shaken out with 
water and concentrated by distillation and the residue recrystallized from 
hot alcohol (85 per cent) and decolorized by boiling with animal-charcoal. 

Digitalin 

Digitalin, C35H56O14, occurs as a white amorphous powder, or in 
characteristic, granular masses. It melts at 217° C. and becomes yellow. 
It is soluble in 1000 parts of water and in 100 parts of 50 per cent alcohol, 
but nearly insoluble in ether and chloroform. Digitalin dissolved in 
alcohol and treated with very dilute acid and heat yields digitaligenin 
and two sugars. 

With concentrated sulphuric acid digitalin forms a golden-yellow solu- 
tion which on the addition of potassium hypobromite solution changes 
to a magnificent rose red or violet red. 

If dissolved in 3 to 4 mils of glacial acetic acid to which a trace of 
ferric chloride solution has been added and the mixture carefully under- 



318 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

laid with concentrated sulphuric acid a deep carmine-red band appears; 
the lower layer of the acetic acid is light yellow, changing to brownish 
(Keller's reaction). 

Sulphuric acid containing a little lerric sulphate gives at first an intense 
golden-yellow color, and then a red solution; this color rapidly changes 
to a beautiful and permanent violet. If too much digitalin is used the 
red color remains and only the surface layer becomes violet. 

If digitalin is stirred to a thin paste with water and for every 100 parts 
of water used 22 parts of amyl alcohol is added with shaking, and the mix- 
ture set aside in a closed vessel for twenty-four hours, the presence of 
digitonin will be indicated by the formation of distinct masses of crystals. 

On hydrolysis with alcoholic hydrochloric acid dextrose, digitalose, 
CtHmOs) and digitaligenin, C22H30O3, melting 210-212°, are formed. 

Kiliani's method of preparing digitalin from German " digitalin " is 
as follows: 

To a solution of one part German digitalin in four parts of 95 per cent 
alcohol, five parts of ether by weight (sp. gr. 0.720) are added and the 
mixture allowed to stand in a closed vessel for twenty-four hours. In 
the clear supernatant solution the quantity of dissolved substances is 
estimated and the whole then subjected to a vacuum distillation until 
its weight becomes 1.6 times that of the total dissolved substances. To 
this concentrated solution water, in an amount 2.4 times the weight of 
dissolved substance, is added, forming a solution containing approxi- 
mately 20 per cent alcohol, from which crude digitalin gradually separates 
on standing. The crude product is washed first with 10 per cent alcohol 
and then with water, and finally dried at a moderate temperature. Further 
purification is effected by boiling the alcoholic solution with animal 
charcoal. 

Digitonin 

Digitonin, C27H46O14+5H2O or C54H92O28 or C55H94O28, is a saponm- 
like glucoside and crystallizes in colorless needles or thick, warty masses 
which dissolve in 600 parts of cold water and 50 parts of warm water to 
a turbid solution, but dissolves to a clear solution in 50 parts of 50 per 
cent alcohol. Its solutions are lsevorotatory. When heated in alcoholic 
solution with hydrochloric acid it is split into dextrose, galactose, and 
digitogenin, C30H48O6 or C31H50O6. It is slightly soluble in absolute 
alcohol and still less in ether or chloroform. 

Concentrated sulphuric acid dissolves it with a red color which is inten- 
sified by the addition of a drop of bromine water, though Jleichard states 
that there is no color with pure sulphuric acid. 

Concentrated hydrochloric acid dissolves digitonin without color, but 



GLUCOSIDES 319 

the solutions become yellow and finally reddish-violet on heating or on long 
standing. 

Keller's reaction gives a rose-red zone whicn soon fades. 

Reichard has found that if an evaporated solution of cobalt nitrate is 
rubbed with digitonin and glacial acetic acid and allowed to stand twenty- 
four to thirty-six hours, rose-red transparent hexagonal crystals are 
formed. 

Digitonin combines with a molecule of cholesterol in alcoholic solu- 
tion to give a crystalline precipitate and is then readily separated from 
digitalin. 

The presence of digitonin in aqueous infusion causes a partial solution 
of digitalin and digitoxin though these glucosides in the pure condition 
are practically insoluble in water. 

Digitonin is separated from German digitalin by the addition of ether 
to the alcoholic solution. The precipitate is dissolved in 10 parts of 85 
per cent alcohol and the solution put into water at 45° C. After stand- 
ing from six to eight hours the greater part of the digitonin will crystal- 
lize out. 

The researches on digitonin by Schmiederberg and Kiliani indicate 
that there may be two forms of the glucoside, and Kraft considers them 
different substances and suggests the name digitsaponin for the Schmieder- 
berg body. 

Gitalin 

Gitalin is a glucoside recently described by Kraft. It is obtained from 
the leaves by extraction with water, and removed from the aqueous 
decoction by chloroform after clarification with lead. The chloroform 
solution, after shaking out with sodium carbonate and then with anhydrous 
sodium sulphate, is poured into petroleum ether whereby the glucoside 
is precipitated. It is an amorphous white powder permanent in the air, 
melting 150-153°, soluble in 600 parts of cold water which subsequently 
decomposes it, less soluble in hot water, readily soluble in chloroform and 
alcohol, and decomposed by ether and carbon bisulphide. It gives a 
crystalline hydrate when dissolved in alcohol and treated with water. 
When dried in vacuo and allowed to remain in contact with alcohol, acetone, 
or chloroform it is apparently converted into a new glucoside, melting 
253°, and to which the name anhydrogitalin is given. 

An aqueous solution of gitalin froths on shaking and gives a precipitate 
with tannin. It gives a violet color with sulphuric acid containing a 
trace of ferric chloride. When dissolved in glacial acetic acid containing 
a trace of ferric chloride and then allowed to run down onto a concentrated 
sulphuric acid containing ferric chloride, the acid becomes indigo and 
the zone of contact violet. 



320 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Gitonin 

This glucoside is less soluble in 95 per cent alcohol than digitonin 
and can be partially separated by solvent. It decomposes at 272° C. 
and has (a) D = —50.69° in pyridin. When hydrolyzed by acids it yields 
gitogenin, a galactose, and a pentose. 

Digitalein 

Digitalein is a Schmiederberg product which seems to be closely related 
to digitonin. It is a water-soluble cardiac poison with a lactone group 
in the molecule. Further study seems desirable before accepting this 
body as a chemical individual. 

COMMERCIAL PREPARATIONS 
Digitalin, " French " — Homolle's Digitalin 

Digitalin, French, is a mixture obtained from Digitalis purpurea by 
the method of Homoile, consisting mainly of digitalinum verum, Kiliani. 

Powdered digitalis leaves are moistened with water and slowly exhausted 
in a percolator. This is precipitated with 250 parts of lead acetate 
and the filtrate from the precipitate treated with 40 parts of crystallized 
sodium carbonate and 20 parts of sodium ammonium phosphate, in order 
to remove the excess of lead. The filtrate is precipitated with 40 parts 
of tannic acid. The tannate is mixed with 25 parts of powdered litharge 
and 50 parts of purified animal charcoal and dried. From the dried mass 
the Digitalis bodies are extracted with 90 per cent alcohol, the latter is 
distilled off and the residue washed with distilled water and again taken 
up in 90 per cent alcohol. This is again distilled and the residue exhausted 
with chloroform. On expelling the latter the digitalin remains behind. 

French digitalin is a yellowish-white, amorphous powder of a peculiar 
aromatic odor and bitter taste. It is neutral to litmus, almost insoluble 
in water, soluble in alcohol and chloroform and insoluble in ether. It 
softens at 90° C. and begins to melt at 100° C. It is not precipitated 
by solutions of lead salts; but with tannic acid, it forms a tannate insol- 
uble in water. It is colored emerald green by concentrated sulphuric 
acid. 

Concentrated sulphuric acid dissolves digitalin, French, producing a 
yellow color, which finally goes over to an emerald-green color. 

Digitalin, German 

Digitalin, German, is a mixture of glucosides obtained from Digitalis 
seeds according to the process of Walz, and consisting largely of digitonin, 
with digitalin verum and other glucosides. 



GLUCOSIDES 321 

Digitalis seeds are extracted with alcohol, the alcohol driven off, the 
extract diluted with water and purified by precipitation with lead acetate. 
The filtrate is freed from lead by sodium phosphate. From the liquid 
thus purified the Digitalis bodies are precipitated with tannic acid, the 
tannate well washed with water and decomposed with lead or zinc acetate. 
The digitalin thus separated is taken up in alcohol, the latter carefully 
distilled off and the residue washed with ether as long as it takes up any- 
thing. The digitalin purified in this way is dried at a low temperature 
and finally powdered. 

German digitalin is a yellowish-white, amorphous powder, soluble in 
water and alcohol, insoluble in ether and chloroform. It is said to con- 
tain about 50-60 per cent of digitonin and 5-6 per cent of digitalinum 
verum, the remainder being digitalein and other glucosides. 

Sulphuric acid containing a trace of ferric sulphate produces with 
digitalin, German, an intense golden-yellow coloration, changing to red 
and finally to a permanent reddish-violet. 

The identification of the individual digitalis glucosides in drug mix- 
tures is complicated by the difficulty of separating them from each other 
in a condition of absolute purity. It is not difficult, however, for the 
analyst to obtain a sufficient number of characteristic tests to assure him- 
self of the presence of these substances in any mixture with which he is 
confronted. Digitoxin and gitalin are both soluble in chloroform and 
are removable from aqueous mixtures by that solvent, and though digi- 
toxin alone is insoluble in water it always occurs in decoctions or extracts 
of the drug due to the influence of the other glucosides. 

In the general scheme of analysis digitoxin and gitalin and perhaps 
a little digitalin will appear in the fraction obtained by shaking out the 
acid aqueous solution with chloroform. A portion of the residue left on 
evaporation of the solvent, dissolved in concentrated sulphuric acid and 
the acid exposed to the fumes of bromine will develop a pink or purplish- 
pink color, and another portion treated with sulphuric acid containing a 
trace of ferric chloride will develop a violet color if Digitalis glucosides 
are present. An aqueous solution will give a precipitate with tannin. 
Reactions described above in detail under the individual glucosides should 
then be applied. 

Digitoxin and gitalin can be estimated with fair accuracy by proceed- 
ing along the fines suggested by Keller in his assay method for Digitalis, 
but there is no chemical method for quantitatively determining the strength 
of so-called " digitalin " in pills or tablets containing declared amounts 
of this substance or in mixtures of other drugs. 

Martindale x describes a chemical method by which he claims it can 
be readily ascertained whether a tincture of Digitalis is up to the physio- 

1 Pharm. J., 1912, 35, 745 and 778. 



322 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

logical requirements. Ten mils of the tincture are mixed with 10 mils 
of water and precipitated with 3 mils of 10 per cent lead acetate solution, 
a little kieselguhr being added. After standing for fifteen minutes the 
precipitate is filtered off and washed. The lead is removed from the fil- 
trate by 2 mils of 10 per cent sodium phosphate and the filtrate evapo- 
rated to dryness after the addition of .2 gram calcium carbonate. The 
residue is mixed with sand and extracted five times with 10-mil portions 
of chloroform. On evaporating the chloroform the residue is extracted 
with 10- and 5-mil portions of water, using sand, and the filtrate evapo- 
rated to dryness and extracted with 5-mil portions of chloroform as before. 
The chloroform solution is evaporated and the residue dissolved in 4 mils 
of glacial acetic acid; 0.1 mil of the acid solution is mixed with 1 mil of 
sulphuric ammonium molybdate solution in a 5X1 cm. test-tube and the 
depth of color produced after five minutes is compared with a standard. 
The coloration indicates the content of combined active water-soluble 
glucosides. 

GLUCOSIDES OF CONVALLARIA 

The root and rhizome of Convallaria majalis (Liliacese) contain gluco- 
sidic substances resembling those present in Digitalis and possessing heart 
tonic and diuretic properties. The drug does not enjoy the wide range 
of usefulness as does Digitalis, but its presence may be suspected in the 
same class of preparations. 

The flowers and the herb are also credited with active properties and 
their extracts find a place in the materia medica. 

Two glucosidic substances have been isolated from the drug. One 
of these, convallarin, is slightly soluble in water and renders the solution 
acrid and frothy. It is readily soluble in alcohol. Convallamarin is 
readily soluble in both alcohol and water. Neither of these glucosides 
is precipitated by basic lead acetate, but convallamarin is thrown down 
by tannin and by this means can be separated from convallarin. 

In working with drug mixtures, an alcoholic solution may be precipi- 
tated by lead subacetate, filtered, the excess of lead removed and the fil- 
tered liquid freed of alcohol, and precipitated by tannin, the solution being 
neutralized by a little sodium carbonate. The tannin compound of con- 
vallamarin is then dissolved in 60 per cent alcohol, decomposed with zinc 
oxide, filtered and evaporated to dryness. If contaminated with salts 
it may be dissolved in alcohol and filtered. 

Convallamarin will be removed from an acid aqueous solution to a 
very slight extent by ether and chloroform, and a dry residue containing 
it will give a brown to purple color with concentrated sulphuric acid. 
The greater proportion of the glucoside will remain in solution after the 



, 



GLUCOSIDES 323 

shaking out process with immiscible solvents is completed. Convallarin 
being but slightly soluble in aqueous liquids will be left behind in the 
evaporated alcoholic residue which has been extracted with water. 

SQUILL 

The bulb of Urginea maritima syn. Scilla maritima (Liliacese) furnishes 
the drug known as squill, which is highly esteemed as an expectorant 
and enters into the composition of cough syrups. It is also employed as 
a diuretic. The common form of croup syrup, the Hive Syrup of the 
Pharmacopoeia contains squill, senega, and tartar emetic, and this is 
sometimes modified in proprietary preparations by the addition of honey 
and tolu and often morphin or other opiates, and vinegar. The acetic 
acid extract of squill is an official preparation. Powdered squill is com- 
bined in pills and tablets with Digitalis and potassium nitrate; some- 
times with buchu; with ipecac and ammoniacum; with mercury mass 
and Digitalis; with ipecac and camphorated opium, sometimes with 
ammonium carbonate and senega; with white pine bark, wild cherry, 
senega, ipecac, Sanguinaria, opium, potassium nitrate, and methyl salicy- 
late; with ammonium carbonate, ammonium bromide, senega, aconite, 
Grindelia and guaiac. 

The chemistry of squill is in an unsatisfactory state. Scillain, scilla- 
toxin, scillipikrin and scillitin, indefinite or glucosidic substances, have 
been reported, but none have been obtained in a condition of purity, 
nor have their individualities been demonstrated. 

Kopaczewski * claims to have isolated three substances, one possess- 
ing diuretic properties, the second a polysaccharide and the third bitter 
and extremely poisonous. The latter, probably a glucoside, appears to 
be a fight, yellowish non-crystalline powder of distinctive odor, soluble 
in alcohol, acetone, acetic acid, and slightly in water. 

Extracts of squill yield nothing characteristic in the usual examina- 
tions with immiscible solvents, and the presence of this drug is not easy 
to determine. Liquid mixtures containing squill are usually heavy syrups 
and on standing a greenish scum collects on the surface of the liquid, 
especially where it touches the glass of the container. The presence of 
acetic acid in the mixture is a further indication that extract of squill 
has been employed in its makeup. Neither of these indications is of 
much value, however, if the analyst is obliged to present the results of 
his investigations before a jury, especially if the opponents are unwilling 
to admit the composition of the product, nor can he place any dependence 
on physiological tests as a means of identification. 

Powdered squill is used as an ingredient of rat poisons and in toxi- 
1 Compt. rend., 158, 1520. 



324 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

cological investigations where the absence of other easily recognized 
poisons has been demonstrated, the presence of squill may be suspected. 

APOCYNUM CANNABINUM. INDIAN HEMP 

The roots of certain species of Apocynum (Apocynaceae) contain a 
principle having a distinct emetic, diuretic, and cardiac tonic action. It 
was hoped that the drug could be used as a substitute for Digitalis in cer- 
tain ailments, but there was considerable uncertainty attending its admin- 
istration in the early days of its use and it failed to attain the reputation 
hoped for it. The conflicting testimony as to its physiological activity 
may have resulted from carelessness in selecting the species used for test- 
ing. The dog-banes and the Indian hemp resemble one another in appear- 
ance and an unskilled collector might easily mistake one for another when 
digging the root. There may be no significance in this explanation, how- 
ever, because recent investigators on the chemistry of A. cannabinum and 
A. androsaemif olium have shown that they both contain the active principle 
referred to above. Dr. Rusby suggests that possibly A. pubescens has 
yielded the drug which has been favorably reported upon. 

An extract of the Apocynum root is used in dropsical affections anol 
Bright's disease. It is combined with a variety of other botanical drugs 
including Podophyllum, Colocynth, Hyoscyamus, Cascara, Juglans, Nux 
Vomica, Gentian, Taraxacum, Capsicum, and Eupatorium. 

Moore, working on A. androsaemif olium and Finnemore on A. can- 
nabinum, isolated the emetic and cardiac-tonic principle. Moore ascribes 
to it the formula, C28H36O6 • 2H2O, and calls it a^o^ynamarm^and Finne- 
more gives it C20H28O6 and calls it cynotoxine. Moore thinks that the 
substances are probably identical, as the physiological properties studied 
independently were practically the same. 

Apocynamarin is intensely bitter and highly toxic. The crystals from 
dilute alcohol melt with decomposition at 170-175°. It is soluble in alco- 
hol and water, but is not removed from an aqueous solution by ether. 
It gives no precipitate with basic lead acetate. When dissolved in acetic 
anhydride and treated with sulphuric acid, a red color is obtained, chang- 
ing to blue and green with a reddish-bronze fluorescence. 

It is possible that apocynamarin is the dilactone of Kiliani's oxydigi- 
togenic acid, C28EU0O6, or an isomeride. 

Moore also isolated[aceto-vanillone\and its glucoside, (androsi mj The 
former is 4-hydroxy-3 methoxy"acetophenone, C9H10O3, melting li2-114°, 
soluble in alcohol and water, and removed from the latter by ether. 

Androsin is a 0-glucoside, CH3 -CO -Cells (O-CHs) -O-CeHnOs, melt- 
ing 218-220°, readily soluble in hot water and hot dilute alcohol, sparingly 
in cold water and absolute alcohol. It is hydrolyzed by emulsin. Its 
acetyl derivative melts 154°. 



GLUCOSIDES 325 



THE SAPONIN-CONTAINING DRUGS 



n 



The saponins form an interesting group of glucosides which are dis- 
tributed widely throughout the plant kingdom. Their chemistry has not 
been fully developed as yet, but attention has been directed to them of 
late because, due to their characteristic property of producing a frothy 
mixture, they have been employed as foam-producing media in beverages, 
and some experiments have indicated that they possess considerable 
toxicity. Hence, investigations Yvdth the pure substances have been 
instituted in order to settle this point. 

From a chemical standpoint, the properties of certain drugs are depend- 
ent on one or more saponin-like ingredients, though, except under certain 
favorable conditions, it is impossible to differentiate between the saponins, 
and thus identify the specific drug which is present in a mixture. The 
two most important drugs are the roots of sarsaparilla and senega; those 
of lesser moment being quillaia or soap-tree bark and the soap-wort, 
Saponaria officinalis. Ginseng also contains a saponin, and Digitalis 
contains digitonin which has the characteristics of a saponin. As was 
observed above, it is seldom possible to identif}' the drug by its saponin 
when in admixture with other ingredients, but the use for which the prepa- 
aration is intended, and the presence of some other well-recognized con- 
stituent in the drug will sometimes aid in establishing its identity. For 
instance, sarsaparilla is almost always employed as an alterative and often 
dispensed with iodides and licorice, while senega is used as an expectorant 
and is accompanied by squill, ipecac, and tartar emetic, and the drug 
contains a small quantity of methyl salicylate. 

The saponins may be divided into two groups, neutral and acid, the 
former being quite extensive. The acid saponins are precipitated from 
aqueous solution by lead acetate, and the neutral by basic lead acetate. 
Most of them are precipitated by barium hydroxide. From a plant 
decoction the tannins and coloring matter may be thrown out first by 
magnesium hydroxide, which does not precipitate the saponins. They 
hydrolyze to sugars and sapogenins; on careful decomposition some give 
first a primary sapogenin and sugar, and on further treatment an endo- 
sapogenin and more sugar. They unite with cholesterol, phytosterol, 
and lecithin. A large number, including quillaic acid, smilasaponin, 
sarsaponin, and parillin, belong to a series having the general formula 
C n H2n-80io, and others, including digitonin and chamaelirin, to the 
group C n H2n-iG02s- Some secondary glucosides from saponir have the 
formula C ra H2 n -607; several endosapogenins have the sapogenin formula 
C n H2n-602, while others contain one more or one less oxygen atom. 

Saponins are either soluble in cold water, alkaline water or water 
containing water-soluble or impure saponins. Their solutions froth strongly 



326 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

when agitated, but acids and alcohol interfere with this foam-producing 
property. They are, as a rule, insoluble in cold absolute alcohol and the 
ordinary organic solvents, but dissolve in hot alcohol, especially if diluted. 
Their aqueous solutions reduce the salts of the heavy metals, gold and 
mercuric chlorides, ammoniacal silver nitrate, ferric chloride, and potas- 
sium ferricyanide, and decolorize permanganate. With copper in alkaline 
solution a green gelatinous compound is produced which is soluble in 
water. A saponin residue develops a red to violet color with concentrated 
sulphuric acid, especially on warming, the solution becoming fluorescent. 

Saponins react with acetic anhydride to form acetyl compounds. On 
hydrolyzing the acetyl body with barium hydroxide and decomposing the 
barium compound with carbon dioxide, a saponin is recovered which, 
however, usually differs from the original substance by being non-toxic, 
though its chemical properties are unchanged. Kobert has suggested the 
designation sapotoxin for the poisonous saponins, reserving the name 
saponin for the physiologically inactive substances. 

Commercial saponin is prepared from the bark of Quillaia Saponaria, 
soap bark, and is a mixture of quillaic acid and quillaia sapotoxin, with 
inert material. It is stated to consist mainly of a non-poisonous modi- 
fication of the first named substance. Commercial saponin is used as 
an emulsifying agent in pharmaceutical mixtures. 

Sarsaparilla 

The drug sarsaparilla is derived from several species of Smilax, of 
which the U. S. Pharmacopoeia recognizes four. Smilax medica, S. ornata, 
S. papyracea, and S. officinalis. These are woody or herbaceous vines, 
with short rhizomes and long roots which are the parts used in medicine. 
There seems to be some confusion in the botanical origin of the different 
classes of sarsaparilla, and the authorities are themselves ambiguous. 
Thus Kraemer states in one place x that S. officinalis yields the Jamaica 
variety and thab nothing is known of the plant yielding Honduras sarsa- 
parilla, yet later in his work 2 he classifies the four commercial varieties 
as follows: 1. Honduras, yielded by S. officinalis growing in Guatemala, 
Honduras and Nicaragua and exported from Honduras and Belize; 2. 
Para, yielded by S. paypracea, growing in the upper Amazon region and 
exported from Para; 3. Mexican, yielded by S. medica, growing in Mexico 
and exported from Vera Cruz and Tampico; and 4. Jamaica or Central 
American, yielded by S. ornata, growing in Colombia, Costa Rica and 
Nicaragua and shipped to Jamaica, whence it is exported chiefly to Eng- 
land. The Honduras and Mexican varieties are chiefly used in the United 
States, the Para to a limited extent. 

1 Kraemer, Botany and Pharmacognosy, p. 238. 

2 Ibid., p. 446. 



GLUCOSIDES 327 

Among the adulterations of this drug which present difficulty of 
identification roots derived from Philodendror species have been reported. 

Sarsaparilla will be found in liquid mixtures recommended for scrofu- 
lous affections and cutaneous diseases, chronic rheumatism, secondary 
syphilis, and conditions following the imprudent use of mercury. It is 
usually a component of the so-called " Blood Tonics." These liquid 
preparations will contain, in addition to Sarsaparilla, Taraxacum; sassa- 
fras, guaiacum, licorice, and Mezereum; potassium iodide; sassafras, 
licorice, anise, and methyl salicylate; senna, stillingia, yellow dock, Podo- 
phyllum, Xanthoxylum, sassafras, licorice, potassium, and iron iodides, 
celery, red clover, Stillingia, cascara, blackhaw, and bromides. These 
types are characteristic, some preparations will include all of the ingredi- 
ents mentioned in a type, and there will be, of course, others where some 
of the drugs are omitted. 

Three saponin-like substances have been reported as occurring in 
sarsaparilla — parillin, smilasaponin, and sarsasaponin. 

Parillin, C26H44O10, is crystalline, melting 177°, (a) D — 42°, and forms 
a penta-benzoyl derivative melting 76°. When hydrolyzed, it yields 
two sugars and parigenin, C28H46O4, a colorless crystalline insoluble sub- 
stance. It is sparingly soluble in cold water, but dissolves readily in 
hot water and slightly in diluted alcohol. 

Smilasaponin, (C2oH320io)5, is a kevorotatory, amorphous substance, 
giving a penta-benzoyl derivative and a sapogenin, C28H46O4. 

Sarsasaponin, (C22H360io)i2, is crystalline, melting 223°, readily sol- 
uble in water and absolute alcohol, and hydrolyzing to sarsasapogenin, 
C28H46O4. 

Power and Salway * working with Jamaica sarsaparilla (S. ornata), 
conclude that it contains but one saponin-like glucoside, sarsasaponin, to 
which they give the formula, C44H76O207H2O, melting 248°, (a) D — 48.5°, 
which on hydrolysis yields one molecule of sarsasapogenin, C27H42O3, 
melting 183°, (a)z>— 60.3° in methyl alcohol, and three molecules of dex- 
trose. They also report a sitosterol-rf-glucoside, C33H36O6, melting 280.5°, 
sitosterol, C27H46O, melting 135-136°, (a) -27.3° in chloroform; stig- 
masterol, C30H50O; sarsapic acid, C4H20(COCH)2, melting 305°, palmitic, 
stearic, behenic, oleic, and linolic acids, and potassium nitrate. The total 
quantity of matter extracted bjr alcohol was equivalent to about 1.25 per 
cent of the weight of the root. They conclude by stating that commercial 
smilacin, the smilasaponin of V. Schulz, is a mixture of a small amount 
of sarsasaponin with indefinite amorphous products. 
1 Chem. Soc. Trans., 1914, 105, 201. 



328 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Quillaja. (Soap Bark) 

Quillaja saponaria is a large tree indigenous to Chile and Peru. The 
bark, which is removed in large pieces and deprived of its periderm or 
other layer, is the official drug. 

The bark of Q. paeppigii is sometimes substituted for the official drug. 

Soapbark is the principal source of the commercial saponin, but it 
finds a place in medicine as a substitute for Polygala senega. 

Quillaic acid, C19H30O10, is precipitated by neutral lead acetate. It 
may be separated from an aqueous extract of the bark, or from medicinal 
mixtures by precipitating as the lead compound, decomposing the latter 
by hydrogen sulphide in the presence of water which dissolves the quillaic 
acid, filtering, concentrating nearly to dryness, adding hot absolute alco- 
hol, and then chloroform to precipitate the coloring matter. On filter- 
ing and allowing to stand the glucoside separates. It is soluble in alcohol 
and water, but does not dissolve in ether. It gives a dark-red color with 
sulphuric acid. When purified by baryta or the acetyl method any toxic 
properties it may have had apparently disappear, but its chemical reac- 
tions are unchanged. This may be due to the fact that the crude material 
occludes some sapotoxin, though the latter is supposed to be soluble in 
presence of neutral lead acetate. 

Quillaja saponin is not precipitated by neutral lead acetate and will 
be found in the filtrate from the precipitation of quillaic acid. It is a 
toxic substance and differs from quillaic acid by giving a yellowish color 
with sulphuric acid, changing slowly to reddish. It is soluble in water 
and alcohol. 

Senega. Snakeroot 

The root of Polygala senega (Polygonacese) is a drug indigenous to 
the United States, and is a popular remedy for croup and diseases of the 
bronchial passages. It possesses expectorant and diuretic properties, and 
will therefore be found in preparations intended for chronic catarrh, croup, 
bronchitis, pneumonia, asthma, rheumatism, dropsy, and amenorrhea. 
An extract of the root is the form in which this drug is dispensed. It is 
usually combined with ipecac or squill in liquid mixture and to those 
will often be added Cimicifuga racemosa (Black cohosh), wild cherry, 
tartar emetic, and licorice. Other combinations will contain in addition 
to senega, white pine bark, wild cherry, squill, ipecac, Sanguinaria, opium, 
potassium nitrate, and methyl salicylate, tar, wild cherry, and verba santa; 
squill, aconite, Grindelia, guaiac, ammonium carbonate, and bromides; 
ammonium chloride, squill, and opium; and in some tablet combinations 
with Hyoscyamus, licorice, tolu, cubeb, ipecac, and ammonium chloride. 

Senega contains two saponins which are similar to those present in 



GLUCOSIDES 329 

Quiliaja bark. Polygalic acid is precipitated by neutral lead acetate, and 
gives a ruby-red color with concentrated nitric acid, finally becoming 
yellow, and yellowish red; it gives a red to violet with concentrated sul- 
phuric acid. It is slightly soluble in chloroform and from an acid solution 
is removed to a slight extent by that solvent. Senegin is the sapotoxin 
and is analogous to the Quiliaja sapotoxin. It gives a yellow color with 
nitric acid. 

Methyl salicylate is present in the drug and apparently increases with 
age. Preparations of which senega is a component will often indicate the 
drug by the presence of this ester. 

Senega saponin, which consists probably of a mixture of polygalic acid 
and senegin, is used sparingly as a remedial agent. 

Saponaria officinalis. Soapwort 

While the root of this plant usually constitutes the drug, the entire 
herb is sometimes used in the form of a decoction. The root may be used 
as an alterative in the place of sarsaparilla. Its chief use is in venereal 
and cutaneous diseases, but it is also employed as a diuretic and diaphoretic. 

The mixed glucosides resemble the crude saponin obtained from 
Quiliaja. They produce sneezing and are soluble in water and hot alcohol, 
separating from the latter on cooling. 

Rosenthaler and Strom x in reporting an investigation of Soapwort 
saponin assign the plant to the Gypsophilse. As this genus is close to 
the Saponaria3 and both are in the Caryophyllacese family the results of 
this research may be inserted at this point. On heating the saponin with 
3 per cent sulphuric acid till a portion of the liquid gave no precipitate 
on further heating, the precipitated pro-sapogenin melted 207° on crystal- 
lizing from alcohol, and gave a semicarbazone, melting 241°. The pro- 
sapogenin when heated under pressure with 2 per cent sulphuric acid gave 
C24H34O5, melting 267-268°, (a) D = +90.86° in alcohol at 18° C. This 
substance was insoluble in water, but dissolved in organic solvents. Its 
semicarbazone melted 259-260°, and on oxidation with alkaline perman- 
ganate it yielded assymetric dimethylsuccinic acid, melting 130-131°. 

The spikenard, Aralia racemosa, and wild sarsaparilla, Aralia nudi- 
caulis, are two drug plants which may be mentioned in connection with 
this group, though their chemistry has never been the subject of research. 

The rhizome of the spikenard furnishes the drug, and it is used as a 
gentle stimulant, diaphoretic, and alterative in chronic rheumatism, 
syphilis, and cutaneous affections. Certain well-known syrups and 
liquid mixtures contain the extract of spikenard with horehound, San- 
guinaria, wild cherry, comfrey, and Inula helenium (elecampane); also 
1 Arch. Pharm., 1912, 250, 290. 



330 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

with morphin, white pine bark, sassafras, wild cherry, Sanguinaria, and 
balsam poplar buds. 

Aralia nudicaulis is a gentle stimulant and diaphoretic and is some- 
times substituted for Sarsaparilla. 

A closely related plant, Ginseng, Panax quinquifolium, furnishes a 
drug which though employed to a slight extent only in this country, is 
exported to China in enormous quantities. The wild plants have become 
so scarce and the demand for the drug so enormous that properly managed 
ginseng plantations are sources of great revenue to the owners. Ginseng 
seems to possess the alterative and diaphoretic characteristics of other 
saponin-containing drugs. 

Caulophyllum thalictroides. Blue Cohosh 

The root of the blue cohosh (Berberidacese) is a valuable uterine tonic 
drug and is used to a considerable extent in so-called " Female Remedies," 
where it is usually combined with Helonias, Viburnum opulus, V. pruni- 
folium, Aletris, and Mitchella. These mixtures are prepared in the form 
of elixirs, cordials, wines, and tablets. A partially purified solid extract, 
is called caulophyllin. Emmenagogue compounds are composed of caulo- 
phyllin, ergot, savine, Polygonum punctatum (water pepper), and other 
drugs commonly used for the purpose. 

Power and Salway * have made an exhaustive study of the drug and 
their results are summarized as follows: 

An alcoholic extract of the ground material, when distilled in a current 
of steam, yielded a small amount of a pale yellow essential oil. From the 
alcoholic extract, the following definite compounds were isolated: (1) A 
crystalline alkaloid, Ci2Hi 6 ON 2 (m.p. 137°; (a) D — 221.6°), which has been 
identified as methylcyt isin ; the pier ate melts at 228°. (2) A crystal- 
line glucoside, caulosaponin, C54H88O17, 4H2O (m.p. 250-255°), which 
yields a deca-aceytl derivative, C54H7sOi7(CO • CH3)io, melting at 135-140° 
and on hydrolysis is resolved into caulosapogenin, C42H66O6 (m.p. 315°), 
and dextrose. Caulosapogenin yields a teTra-acetyl derivative, C42H62O6 
(CO -0113)4, melting at 120°, and a diacetyl derivative, C42H640e(CO- 
CH3)2, melting at 160-162°, from which a c^stalline monosodio-deriva- 
tive, C42H630eNa(CO -0113)2, was prepared; it yielded, furthermore, a 
tetrabenzoyl derivative, C42H620e(CO • CeHs)^ melting at 288°, and a mono- 
methyl ether, C42H6505(0 • CH3), which melts at 235°. (3) A new crystal- 
line glucoside, caulophyllosaponin, C66H104O17 (m.p. 250-260°; (a)z>+ 
32.3°), which yields a deca-acetyl derivative, C66H 9 40i7(CO-CH3)io, 
melting at 155-160°, and on hydrolysis is resolved into ^aulojJ ayllias&Ro- 
genin^. C56Hs809(m.p. 315°) and arabinose. Caulophyllosapogenin yields 
1 Trans. Chem. Soc, Vol. 103, 1913, p. 191. 



GLUCOSIDES 331 

a hexa-acetyl derivative, C56H 8 209(CO-CH 3 )2, melting at 160-162°, and 
a dimethyl ether, C56H 8 607(0-CH 3 )2, which melts at 240-242°, and has 
(a)z>+43.6°. (4) A phytosterol, C27H46O (m.p. 153°). (5) Citrullol, 
C2sH4602(OH)3. (6) A mixture of fatty acids, consisting of palmitic, 
stearic, cerotic, oleic, and linolic acids. The alcoholic extract also con- 
tained a quantity of sugar, which yielded d-phenylglucosazone (m.p. 210°), 
and comparatively small amount of resinous material. 

The above-mentioned methyl cytisin, C12H16ON2, represents the alka- 
loid previously obtained by J. U. Lloyd 1 and designated "caulophylline," 
but he did not succeed in crystallizing the base, and its composition 
was not determined. 

The compound designated by the present authors as caulosaponin, 
C54H88O17, 4H2O, is undoubtedly identical with a crystalline glucoside 
first obtained by J. U. Lloyd 2 and termed by him "Leontin," although the 
formula deduced from its analysis was not correct. 

Chamaelerium luteum. Starwort or False Unicorn 

This plant, also known as Helonias, belongs to the Melanthacese and 
is one of our indigenous drugs. It is often confused with Aletris farinosa, 
the star grass or true unicorn root. The two drugs are often gathered and 
mistaken for each other by collectors. Helonias bullata is a closely allied 
plant and belongs to a monotypic genus. 

The root possesses tonic and diuretic properties, and its extract is 
usually one of the constituents of the widely exploited remedies for troubles 
of the female reproductive organs. The Viburnum Compound type of 
preparations contain Chamaelirium, Aletris, Viburnum opulus, and pruni- 
folium, Mitchella repens (Squaw vine) and Caulophyllum thalictroides. 
Some of the mixtures will lack one or more of these drugs, but this is the 
general type. Tablets for leucorrhea, known as Helonias astringent, con- 
tain Chamselirium, Hyoscyamus, Opium, Hamamelis, tannic, salicylic 
and boric acids, alum, thymol, and eucalyptol. 

The root contains a saponin-like substance which, when separated, 
forms a powder of the appearance of acacia, readily soluble in water and 
hot alcohol but not in other organic solvents. The other constituents 
of the drug have not been described. 

Aletris farinosa. Star grass. True Unicorn-root 

Aletris farinosa (Liliaceae) may well be included at this point because 
of its confusion with the previous plant. 

Aletris occurs in uterine tonics of the type mentioned under Chamaeli- 
rium. The chemical constituents of the drug have never been studied. 

1 Proc. Amer. Pharm. Assoc, 1893, 41, 115. 

2 Drugs and Medicines of North America, Vol. II, 1887, p. 151. 



332 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Its recognition in medicinal mixtures can be accomplished with certainty 
only by examining microscopically the insoluble portions, and noting any 
characteristic tissues, which of course must be compared with slides 
obtained from authentic specimens of Aletris. 

The presence of a saponin-containing drug is apparent by the frothing 
of the solution during the manipulation of the mixture while performing 
an analysis. If the preparation is a liquid, and an alcohol determination 
is in progress, the frothing and bubbling will often cause considerable 
inconvenience after the bulk of the alcohol has passed over, and may neces- 
sitate a redistillation of the distillate. 

In the systematic scheme of analysis there will be more or less saponin 
dissolved out by the alcohol and subsequently taken up by water. The 
presence of the saponin will seriously interfere with the extractions of 
alkaloids and other principles by immiscible solvents because of the emul- 
sion formed. This difficulty may be overcome either by shaking out with 
Prolius mixture or by adding basic lead acetate. 

Most of the saponin-like substances, with the exception of small 
amounts of polygalic and quillaic acids, will be left in the aqueous solu- 
tion after the extraction with immiscible solvents. If it is desired to 
separate these substances and subject them to characteristic tests, the 
above-mentioned solution, the original mixture, or an aqueous decoction 
obtained from the sample may be employed. The saponin is first extracted 
in a crude state and then purified. The solution is acidulated if alkaline, 
and then neutralized with magnesium carbonate and 20 grams or a pro- 
portionately less amount of ammonium sulphate are added and 10 mils 
of phenol (carbolic acid) ; after shaking, the phenol solution is separated 
and shaken with 50 mils of water and 100 mils of ether with the addition 
of alcohol if necessary to prevent emulsification; the aqueous layer is 
drawn off and allowed to dry in a desiccator. The residue is then washed 
with acetone or ether and after decanting the liquid, the residue is ready 
for testing. If dextrins are present they should be first removed by con- 
centrating the solution to 20 mils and adding 100-120 mils of 95 per cent 
alcohol; after standing thirty minutes the mixture is boiled on the water- 
bath, filtered, the alcohol evaporated and the residue made up to 100 mils 
and treated as above. 

Another procedure consists in treating the solution with lead sub- 
acetate and centrifuging, decomposing the precipitate with hydrogen sul- 
phide in the presence of water, filtering, evaporating, extracting the resi- 
due with ether, and then dissolving the residue in water, filtering, and 
evaporating. Of course, if the aqueous solution contained sulphuric or 
other strong asids or their salts, the neutralized mixture must first be 
treated with barium chloride to remove them, otherwise their presence 



GLUCOSIDES 333 

would seriously interfere with the evaporation of the nitrate from the 
hydrogen sulphide treatment of the lead precipitate. 

The saponin residue can then be subjected to identity tests. It should 
be divided into fractions by dissolving in water and evaporating 3 to 4 mils 
for the tests with concentrated sulphuric acid, nitric acid and Froehde's 
reagent. Portions of the aqueous solution may be treated with the salts 
of the heavy metals, gold and mercuric chlorides, ammoniacal silver nitrate, 
ferric chloride, permanganate and potassium ferricyanide, which are 
reduced, and with alkaline copper. 

The hemolytic test is applied with a suspension of red-blood corpuscles 
prepared by washing sterile, defibrinated animal blood by centrifuging 
three times with physiological salt solution, and when the solution is clear 
removing 5 mils of the red corpulsces and diluting with 100 mils of the salt 
solution. A portion of the latter, well mixed, is treated with the saponin 
solution, which will cause hemolysis, recognized by the reddening of the 
solution due to the dissolved hemoglobin, and at the same time the cloudy 
suspension becomes clearer. A negative reaction does not necessarily 
mean the absence of a saponin-like body because the separation and puri- 
fication of these bodies appears to change their physiological action, and 
furthermore it appears that those of the saponin class possess in the nat- 
ural state the most pronounced action on the blood. 

The aqueous solution may be further tested by adding hydrochloric 
acid to a strength of 2.5 per cent and then heating on the steam-bath until 
the solution ceases to foam. The pro-saponins thus formed are shaken 
out with ethyl acetate, the solvent washed free of acid, filtered through 
charcoal and evaporated. The residue should give an orange to cherry- 
red color with concentrated sulphuric acid, which on standing changes 
to violet; and its solution in dilute soda should foam on shaking. 

No very reliable methods have as yet been evolved for estimating the 
saponins. The relations of the sapogenins to the sugars is not well under- 
stood, and any quantitative estimation would probably be based upon 
these products of hydrolysis. Korsakoff 1 describes a method for determin- 
ing saponins in plants which might be made applicable to liquid medicines 
and to decoctions prepared from solids. The plant is completely dried, 
pulverized finely and treated with 60 per cent alcohol. After filtration, 
the alcohol is distilled off and the residue evaporated with calcined mag- 
nesia, the magnesia cake is pulverized, exhausted with boiling 80 per cent 
alcohol, filtered, and the filtrate precipitated with ether. The precipitate 
is dissolved in dilute sulphuric acid and hydrolyzed by heating for one 
hour in an autocalve to 100°. The liberated sapongenin is washed with 
water until neutral, dissolved in absolute alcohol, the solution evaporated 
to dryness and the sapogenin weighed. From the weight, the correspond- 
iComptesrend., 1912, 155, 844. 



334 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

ing weight of the saponin can be calculated provided the analyst knows 
the proportion of sugar and sapogenin in the original saponin. 

Carlifanti and Marzocchi x recommend the following method for 
determining saponin in emulsions: 100 mils of the emulsion are diluted 
with an equal volume of water and 400 mils of 95 per cent alcohol added 
gradually with agitation, the mixture being shaken frequently during two 
hours and allowed to stand twenty-four hours. The supernatant clear 
liquid is filtered through linen and the residual oil extracted with 60-65 
per cent alcohol, and this extract also filtered and added to the first filtrate. 
The whole is neutralized with sodium carbonate and concentrated to 
100 mils. A slight excess of phosphoric acid is added and saccharin and 
aromatic substances removed with ether. The residual aqueous liquid 
is treated with 20 grams of ammonium sulphate, and shaken out with 
several successive portions of 9 mils each of phenol. The phenol solu- 
tion is shaken with a mixture of 100 mils of ether, 30 mils of water and 5 
mils of alcohol and after twenty-four hours the aqueous solution is sepa- 
rated, evaporated on the water-bath, the residual saponin washed with 
acetone, dried, and weighed. 

ARBUTIN 

Arbutin is a glucoside which occurs in the leaves of a number of dif- 
ferent species of plants. Certain evergreen plants whose leaves are 
official drugs contain arbutin and their medicinal value is probably depend- 
ent in part at least to its presence. UvaUrsi syn., Arctostaphylos Uva 
Ursi (Ericaceae), bearberry or upland cranberry, and Chimaphila umbel- 
lata (Pyrolacese), pipsissewa or princess pine, are the two official drugs 
characterized by arbutin, and Kalmia latifolia (Ericacese), mountain 
laurel, non-official, also contains the glucoside. Arbutin is present in 
the leaves of other plants of the same families. It occurs in Vaccinium 
Vitis Idsea ( Vacciniacese) , mountain cranberry or whortleberry, an ever- 
green shrub whose leaves might be mistaken for the Uva Ursi. 

UVA URSI 

This drug is astringent and tonic, especially in those diseases affect- 
ing the urinary organs, hence it may be expected in remedies designed to 
alleviate gleet, nephritis, catarrh of the bladder, incontinence of urine, etc. 

An extract of the drug is dispensed in popular form, and it is commonly 
combined with buchu, juniper berries, cubeb, and nitrous ether in the 
form of fluid extract buchu compound. It will be found in elixirs in the 
same combination, and with matico and Hydrangea. It is also present 
in some of the methylene-blue compounds, and potassium acetate or 
1 Boll. Chim. Farm., 1911, 50 , 609. 



GLUCOSIDES 335 

nitrate and Eupatorium may be added to the above-described combi- 
nations. 

PIPSISSEWA— CHIMAPHILA UMBELLATA 

Pipsissewa is an astringent, alterative, tonic, and diuretic drug, and 
is often substituted for Uva Ursi in remedies designed for the urinary 
tract. Its extract is used in chronic rheumatism and nephritis. It is 
combined with Stillingia in fluid extract stillingia compound, in which is 
also included Bikukulla canadensis, Iris, Sambucus, prickly ash berries, 
and coriander. Elixirs and syrups of this general composition will be 
encountered. 

Chimaphila maculata, the spotted wintergreen, is an evergeren plant 
which grows in the same localities as the above and is often erroneously 
called pipsissewa. 

KALMIA LATIFOLIA 

The extract of mountain laurel has a limited use as an antisyphilitic 
and sedative. It is somewhat astringent and is employed in obstinate 
diarrhea. 

ARBUTIN, C 12 H 16 7 

Arbutin, to which the above drugs owe at least part of their thera- 
peutic value, is also administered as a pure substance for diuretic pur- 
poses and as an urinary antiseptic. 

Arbutin occurs in long, glistening, colorless needles, or as fine white 
crystalline, odorless powder having a bitter taste. It is soluble in 8 parts 
of water and 16 parts of alcohol, and somewhat soluble in ethyl acetate; 
very soluble in hot water and hot alcohol; insoluble in chloroform, ether, 
carbon disulphide. Its aqueous solution is neutral to litmus paper and 
is not precipitated by solutions of the metallic salts or by solutions of 
tannin. Its aqueous solution is colored blue by ferric chloride test solu- 
tion, and when boiled with ferric chloride the pungent odor of quinone 
is evolved. By boiling with diluted sulphuric acid or by treatment with 
emulsin, arbutin is converted into glucose and hydroquinone. 

When heated to 100° C. arbutin loses its water of hydration. At 
195° C. the anhydrous glucoside melts. 

Arbutin probably is accompanied by methyl arbutin in the plant. 
When it is hydrolyzed both the hydroquinone and glucose reduce Fehling's 
solution. Methyl hydroquinone does not reduce Fehling's solution, but 
it does give a blue color with ferric chloride while methyl arbutin does not. 

Arbutin in aqueous solution gives a blue color when treated with a 
solution of 1 gram of sodium phosphomolybdate in 10 mils of concentrated 



336 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

sulphuric acid and 20 mils water (Jungmann's reagent), followed by an 
equal volume of ammonia water. Methyl arbutin does not react with this 
reagent, but methyl hydroquinone does. 

When arbutin is submitted to the action of emulsin, the liquid after 
the second day becomes pink and gradually darker until it is yellowish- 
brown. Under the same conditions a solution of methyl arbutin, if pure, 
will remain colorless for a long time. 

If arbutin is treated in alcoholic solution with potassium hydroxide, 
a precipitate of the alkali with arbutin is obtained. The pure glucoside 
may be separated from this compound by filtering, washing with strong 
alcohol, boiling with glacial acetic acid under a reflux, neutralizing with 
calcium carbonate, distilling off any alcohol, and shaking out with ethyl 
acetate, from which on concentrating the arbutin will crystallize. 

In the general scheme of analysis of medicinal products, arbutin will 
be left in solution after the mixture has been subjected to extraction with 
the different immiscible solvents. If the solution is concentrated, acidified 
with hydrochloric acid, and refluxed, the arbutin will be converted to 
hydroquinone and glucose, and the former may then be shaken out with 
ether and identified. 

SALICIN AND BENZOYLSALICIN (POPULIN) 

Salicin occurs in the bark of the white and black willow, Salix alba 
and S. nigra (Salicacese) and populin in the bark of some of the genus 
Populus, three representatives of which are used medicinally. Salix 
fragilis, crack willow, furnishes considerable of the salicin of commerce. 

Salix alba is the European or white willow, a large tree, native of 
Europe, and introduced into this country. Its bark is used as a tonic, 
febrifuge, astringent, and antirheumatic, but has been largely superseded by 
its glucoside, salicin, which is now prepared in the pure condition and has 
the honor of being the only glucoside recognized in the U. S. Pharmacopoeia. 

Salix nigra, the black or swamp-willow, is native in this country and 
its bark possesses similar properties to that of S. alba. Its buds are also 
used medicinally and are claimed to exert a peculiar sedative influence 
on the sexual organs. 

The barks of Populus alba, white or silver-leaf poplar, and P. tremu- 
loides, quaking aspen, possess tonic, diuretic, and febrifugal properties. 
P. candicans, Balm of Gilead, is a large tree, the leaf buds and barks of 
which are used medicinally. 

Salicin is marketed alone in the form of pills and tablets of different 
strengths from 1 to 5 grains. It is also combined in various mixtures with 
zinc oxide, belladonna, hydrastin, and pepsin; and with caffein, acetphene- 
tidin, and ammonium salicylate. 



GLUCOSIDES 337 

Salicin, C13H18O7, occurs as a crystalline silky powder or white, shin- 
ing, tabular crystals or scales, melting 198-201°. It dissolves readily 
in hot water and hot alcohol, less readily in the cold, and is insoluble 
in the ordinary organic solvents. It is ortho-hydroxy benzyl glucoside, 
CeH^OCeHnC^CH^OH, and on hydrolysis by emulsion yields one 
molecule of saligenin (o-hydroxybenzyl alcohol) and one of glucose. 

Salicin is not precipitated by lead acetate, basic lead acetate, tannin, 
or alkaloidal reagents. Its solution can therefore be clarified by lead, 
filtered, the lead removed by hydrogen sulphide, the solution neutralized 
and concentrated, and the glucoside recovered in part by crystallization 
provided it is present in fair amount. 

The pure glucoside is neutral in reaction, laevorotatory (a) D — 65° in 
aqueous solution. With concentrated sulphuric acid it gives a bright- 
red color which is destroyed by water with the deposition of a deep-red 
powder. When warmed with bichromate and sulphuric acid and then 
treated with water the odor of salicylic aldehyde is evolved. Froehde's 
reagent gives a purple color. Its aqueous solution is not colored by 
ferric chloride. 

When boiled with dilute mineral acids salicin is hydrolyzed to dextrose 
and saliretin, the latter separating as a white substance, removable from 
acid solution by ether and capable of being converted to picric acid by 
nitric acid. If the hydrolysis is performed with emulsin at a temperature 
of 37° C, saligenin and dextrose are produced, and the former may be 
removed by shaking out with ether. It gives an indigo-blue color with 
ferric chloride and its other properties are fully described on page 553. 

In the general scheme of analysis salicin will be left in the aqueous solu- 
tion after the extraction with immiscible solvents, and its presence may 
be detected by the hydrolyzing of the solution with emulsin or by crystal- 
lizing as described above. 

To estimate salicin in pills or tablets, a solution of the sample should 
be hydrolyzed by emulsin at 37° C. and the saligenin removed by ether, 
collected in a tared dish, the solvent evaporated and the residue weighed. 
If sugars are not present the dextrose could be determined and the salicin 
calculated, but most medicines usually contain some reducing sugar, 
which will of course vitiate any results obtained in this way. 

SALINIGRIN, Ci 3 Hi 6 7 

Salinigrin is reported by Jowett : as occurring in the bark of certain 

species of willow. It yields m-hydroxybenzaldehyde and glucose on 

hydrolysis. It melts at 195°, is fairly soluble in cold water, and very 

soluble on warming, sparingly soluble in cold alcohol, but more so in hot 

1 Trans. Chem. Soc, 1900, 707. 



338 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

alcohol, sparingly soluble in hot acetone, almost insoluble in ether, 
petroleum ether, and chloroform. It gives no color reaction with sul- 
phuric acid. It is lsevorotatory (a:)z>i6= — 87.3°. 

POPULIN, C2oH 22 8 

Populin or benzoylsalicin crystallizes with two molecules of water, 
which it loses at 100° C. The anhydrous substance melts 180°. It has 
a sweet taste, resembling that of licorice. It is slightly soluble in cold 
water and fairly soluble on boiling, slightly in alcohol and insoluble in 
ether. Sulphuric acid produces an amethyst-red color. 

When boiled with barium hydroxide solution populin is converted to 
salicin and benzoic acid. Dilute mineral acids produce dextrose, benzoic 
acid, and saliretin. It is unacted upon by emulsin. 

GLUCOSIDES OF THE BLACK HELLEBORE AND ALLIED DRUGS OF THE 

RANUNCULACEJE 

The rhizome of Helleborus niger (Ranunculaceae) , black hellebore or 
Christmas rose, is used principally in female pills and emmenagogues. 
It was formerly used for dropsy and epilepsy, and Bacher's pills for the 
former disorder were reputed to consist largely of this drug. 

The types of female and emmenagogue pills containing black helle- 
bore include in addition ergot or some proprietary preparation of ergot, 
aloes, ferrous sulphate, and oil or extract of savine; aloes, ferrous sulphate, 
Jamaica ginger, myrrh, soap, and Canella alba (cinnamon or whitewood 
bark), which represents the Hooper formula; cotton-root bark, ergot, 
ferrous sulphate, aloes, and savine oil. 

The drug contains helleborin, C36H42O6, a glucoside, forming white 
glistening needles, soluble in alcohol and ether, but insoluble in water. It 
is tasteless in the isolated condition, but in alcoholic solution it produces 
a burning, numbing sensation on the tongue. Concentrated sulphuric 
acid dissolves helleborin with an intense red coloration which gradually 
disappears and a white precipitate separates. It yields glucose and helle- 
boresin on hydrolysis. 

Helleborein, C26H44O15, is found in the seeds and leaves of H. niger, 
but apparently is not present in the root. It forms fine, hygroscopic 
needles which are bitter and cause sneezing. It is soluble in water and 
alcohol, but not in ether, and hence can be easily separated from helle- 
borin. With concentrated sulphuric acid a golden-yellow to reddish- 
brown coloration is obtained. It yields dextrose and helleboretin on hydrol- 
ysis, the latter being a violet blue substance when moist. Helleborein 
may be precipitated from aqueous solution by tannin, but not by basic 
lead acetate. 



GLUCOSIDES 339 

Glucosides of Adonis vernalis 

Adonis vernalis (Ranunculaceae), false hellebore or bird's eye, is a 
European and Asiatic species, the whole plant furnishing a drug having 
diuretic and heart-tonic properties. It is used for these purposes and 
also as a substitute for Helleborus niger. 

It contains helleborein, adonidin, and picradonidin, all glucosides, and 
adonidic acid. Adonidin has been separated in a state of partial purity 
and appears to be an intensely bitter, odorless, hygroscopic substance, 
readily soluble in water and alcohol, but insoluble in chloroform and ether. 
It is not precipitated by either neutral or basic lead acetate, but is thrown 
out by tannin and is therefore readily separated from the adonidic acid 
which gives an insoluble compound with lead. When adonidin tannate 
is treated with zinc hydroxide and alcohol, evaporated to dryness at 40- 
50°, and extracted with absolute alcohol, the adonidin goes into solution. 

Adonidin in its action closely resembles certain of the digitalis gluco- 
sides. 

Adonis aestivalis, a closely allied plant of the same general habitat, 
probably contains adonidin. The drug is used as a remedy for obesity. 

Actea spicata 

The rhizome and rootlets of Actea spicata possess properties similar 
to Hellebore and are sometimes substituted for it. The plant is a native 
of Europe and Asia and is known as the baneberry or white cohosh. 

In the United States we have two species of Actea having a limited 
use as drugs, A. alba and A. rubra. They are closely related to A. spicata, 
which is the type species and are known respectively as white cohosh or 
white baneberry and red cohosh, red baneberry or black cohosh (this term 
is misleading, as the true black cohosh is Cimicifuga racemosa). 

The rhizomes of all these plants are violent purgatives, and according 
to Kraemer the European species contain helleborein. 

Cimicifuga racemosa. Black Cohosh 

The plant furnishing the drug so well known in this country as black 
cohosh or Macrotys is closely allied to the Acteae, and the growing plant 
unless in blossom is readily mistaken for A. alba. Its reputation is depend- 
ent on its properties of relieving headache and uterine pains accompany- 
ing pregnancy, and in re-establishing the menstrual flow. It will con- 
sequently be found in remedies for female troubles. To a lesser extent 
black cohosh is used as a tonic, nervine, antispasmodic, and antirheumatic. 
As an antispasmodic it is employed in St. Vitus dance. It is dispensed 
alone and in combination in pills and tablets with wild cherry, ipecac, and 
licorice ; with morphin and quinin in dysmenorrhea mixtures ; with aloes, 



340 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

cotton root bark, and ferrous sulphate; with Podophyllum resin, leptandra, 
juglans, and Capsicum; with aconite, belladonna, and colchicin; with 
lithium, salicylates, Phytolacca, and colchicin. In liquid mixtures it 
accompanies salicylic acid, potassium iodide, and Gelsemium. It is the 
essential ingredient of the so-called "Mothers' Cordials" or " Parturient 
Balms," and may be accompanied by aconite or Veratrum viride. 

The root was used by the Indians as a remedy for snake bites, and the 
plant is also called black snakeroot. 

The roots of C. Americana and C. cordifolia are undoubtedly often 
substituted for C. racemosa. The three plants grow in the Eastern floral 
section of the United States and the close resemblance of Americana to 
the common drug would be confusing to anyone but a trained drug col- 
lector or botanist. 

The chemistry of the black cohosh rhizome is as yet unreported. It 
contains a resin, which is probably of complex composition. This resin 
is known as macrotin or cimicifugin and will be found listed in the drug 
catalogues under the head of "concentrations." It imparts a sweet taste 
to water, and upon prolonged chewing the taste becomes disagreeable 
and the throat experiences a burning or smarting sesnation. Tannin- 
like substances giving a black color with ferric chloride are present. 

Extracts of fresh root are employed in eclectic practice. They have 
a sweet taste and a golden-yellow color. 

CYANOGENETIC GLUCOSIDES, OIL OF BITTER ALMONDS AND HYDRO- 
GEN CYANIDE 

Wild Cherry Bark and 1-mandelonitrile Glucoside 

Padus virginiana, syn. Prunus serotina (Amygdalacese) the wild black 
cherry, a large indigenous tree most abundant in the Southwestern States, 
furnishes the drug Prunus virginiana or wild-cherry bark. The tree some- 
times attains a height of 90 feet with a maximum trunk diameter of 4 feet 
and is straight, the trunk being covered with a rough black bark, the young 
branches smooth and reddish. It is readily distinguished from Padus 
nana, the common choke cherry, a shrub growing from 2 to 10 feet, and 
from P. melanocarpa, the Rocky Mountain wild cherry, a smaller tree. 

The bark is official in the U. S. Pharmacopoeia and is collected in the 
autumn. The outside layer is first removed, so that the green layer under- 
neath shows. The best grade is known as "thin green," the next grade 
"thick green," and the low grade "thick rossed." 

Wild cherry bark is commonly employed as an ingredient of remedies 
intended for coughs and pulmonary complaints. It will be found in liquid 
White Pine compounds combined with white pine bark, balsam poplar 
buds, spikenard, Sanguinaria, Sassafras, morphin, and chloroform; in 



GLUCOSIDES 341 

sedative cough mixtures with codein, Cannabis sativa, white pine bark, 
Eriodictyon, balsam poplar buds, chloroform, and glycerin; with Erio- 
dictyon, licorice, salicylic acid, Grindelia, pine tar and potassium bromide; 
with Sanguinaria, Marrubium, comfrey, spikenard, Inula, and Ceanothus 
americanus (Jersey tea). Alcoholic extracts of Wild cherry bark intended 
for the preparation of syrups and other purposes, often contain other 
drugs such as Marrubium (Horehound), Veratrum viride, Sanguinaria, 
and wild lettuce; or Cimicifuga, ipecac, licorice, and senega. 

Elixirs intended as tonics and stimulants to the digestive tract will 
be found containing wild cherry, Taraxacum, and licorice; and gentian, 
Taraxacum, Eucalyptus, licorice, and Eriodictyon 

The tablet and lozenge combinations are of the same general type as 
the liquids, thus we often meet with wild cherry combined with white 
pine bark, squill, senega, ipecac, Sanguinaria, opium, camphor, potassium 
nitrate, and methyl salicylate; with terpin hydrate, guaiac, opium, cam- 
phor, and belladonna; with licorice, pine tar, Eriodictyon, and senega; 
with licorice, colts foot, acacia, Marrubium, anise, cubeb. Capsicum, and 
tolu. 

One of the most widely advertised preparations of wild cherry is the 
well-known confection recommended for coughs and colds. These wild 
cherry drops are sold in enormous auantities and consist almost entirely 
of sugar. 

The characteristic glucoside of wild cherry bark is Z-mandelonitrile 
glucoside, which also occurs in the bark of Cerasus padus syn., Prunus padus 
and isomeric with sambunigrin and prulauresin, the /3-glucoside of dextro 
and racemic mandelonitrile respectively. Sambunigrin occurs in the 
leaves of Sambucus nigra, the common black elder and prulauresin in 
the leaves of the cherry-laurel, Prunus lauro-cerasus. 

An aqueous decoction of the bark yields hydrogen cyanide and con- 
tains the cyanogenetic glucoside. 

An alcoholic extract of the bark has been carefully examined by Power 
and Moore. 1 The portion of the alcoholic extract which was soluble in 
cold water contained the glucoside, sugar, tannin, benzoic, trimethyl gallic, 
and p-coumaric acids, and after heating with dilute sulphuric acid, £-man- 
delic acid and jS-methylsesculetin. The alcoholic extract insoluble in cold 
water consisted of two resinous substances, one a greenish body insoluble 
in warm water and the other a brown amorphous product soluble in hot 
water and depositing slowly on standing. The green resin, amounting to 
about 1 per cent of the weight of the bark, yielded a phytosterol, C27H46O, 
melting 135-136°, (a) D — 34.0°; palmitic, stearic, oleic, linolic acids, and 
apparently a very little isolinolenic acid, ipuranol; and after acid hydrolysis 
oleic acid, dextrose, and /3-methylaBsculetin, CioHgO^ melting 204°! The 
1 Trans. Chem. Soc, 1909, 243. 



342 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

brown resin, amounting to about 1 per cent of the weight of the bark, 
jdelded after acid hydrolysis, a trace of a phytosterol, small amounts of 
oleic acid, /3-methyla3Sculetin, dextrose, insoluble red resinous material, 
which on fusion with potassium hydroxide gave formic, acetic, butyric, 
and proto-catechuic acids. 

An alcoholic extract of the bark, when distilled with steam, yielded 
small amounts of benzoic acid and an essential oil, but no hydrocyanic 
acid. The bark contains an enzyme which hydrolyzes ,3-glucosides. 

The separation of the Z-mandelonitrile glucoside in a condition of 
purity is attended with some difficulty and the following method was 
adopted by Power and Moore in recovering it from the drug: 

One kilogram of the original alcoholic extract, representing about 3.8 
kilograms of the bark, was mixed with 2 liters of water, and the volatile 
constituents were removed by distillation with steam. The contents of 
the distillation flask were then filtered while hot from the previously 
described green resin, the latter being thoroughly washed with water, and 
the washings added to the filtrate. After allowing the combined aqueous 
filtrate and washings to stand for several weeks, a quantity of the pre- 
viously described brown resin was deposited, from which the clear liquid 
was decanted. This liquid, being large in amount, was divided into four 
portions, each of which was concentrated as far as possible under dimin- 
ished pressure. To each portion 200 mils of alcohol were then added, 
and, after complete solution, the thin syrups were again concentrated 
under diminished pressure, this operation being repeated until the mass 
became too viscid for further concentration. Each portion was then dis- 
solved in 200 mils of absolute alcohol, and to the thin syrups so obtained 
1 liter of boiling, dry ethyl acetate was added in each case. After stand- 
ing for several hours, the liquids were decanted from the precipitated 
syrup, concentrated to about 100 mils, and while still hot, 500 mils of 
boiling, dry ethylacetate added to each portion. They were again allowed 
to stand for several hours, when some syrupy material was deposited, from 
which the clear ethyl acetate liquids were decanted. These were then 
united, concentrated to the measure of 500 mils, and, after cooling, 500 
mils of dry ether added. The clear liquid was then separated, the solvent 
completely removed, and the residue dissolved in about 300 mils of cold 
water. This aqueous liquid was shaken with small successive portions 
of ether in order to remove the acids which were known to be present, 
after which it was treated with a solution of normal lead acetate until no 
further precipitate was produced. The yellow precipitate was removed 
by filtration with the aid of the pump, and the aqueous filtrate concen- 
trated on the water-bath under diminished pressure to about 30-40 mils. 
A mixture of 300 mils of alcohol and 300 mils of ethyl acetate was then 
added, and the whole allowed to stand overnight. The clear liquid, 



. 



GLUCOSIDES 343 

decanted from a small amount of a yellow precipitate, was concentrated 
to a small volume, the residual product being then dissolved in water and 
treated with hydrogen sulphide for the removal of the lead. After filtra- 
tion, the aqueous liquid was concentrated under diminished pressure to 
the measure of about 50 mils, when an excess of calcium carbonate was 
added to neutralize the free acetic acid, and the mass then extracted with 
alcohol. This alcoholic extract was evaporated to dryness on a water- 
bath under diminished pressure, and the residue dissolved in ethyl acetate, 
when, after concentrating the solution to about 20 mils, the glucoside 
slowly crystallized in small, colorless needles. It was recrystallized from 
ethyl acetate, when two crops of crystals were obtained. The first frac- 
tion of crystals, which amounted to 0.6 gram, melted initially at 144- 
146°, and, after further crystallization, at 145-147°. The second frac- 
tion of crystals, which was very small in amount (about 0.1 gram), was 
somewhat less pure, and melted at 135-140°. Both these fractions, when 
treated with emulsin, yielded hydrogen cyanide, benzaldehyde, and glu- 
cose. The first fraction was analyzed, with the following result: 

0.1392 gave 0.2904 C0 2 and 0.0750 H 2 0. C = 56.9; H = 6.0. CuHiyOeN 

requires C = 5o.9 H = 5.8 per cent. 

0.3605, dissolved in 20 mils of water, gave in a 2 dcm. tube as- 1°4', 

whence (a)z>-29.6°. 

The above described cyanogenetic compound was thus identified as 
Z-mandelonitrile glucoside. 

A determination of the specific rotatory power of the small fraction 
of glucoside melting at 135-140° gave the following result: 

0.0956, dissolved in 20 mils of water, gave in a 2-dcm. tube a D — 0°14', 

whence («)*>- 24.4°. 

It has the composition C 6 H 5 CH(OH)CNC6Hio05, and when pure 
melts 147°, (a) D — 26° or —29.6°, hydrolyzing to dextrose and d-man- 
delonitrile, C6H 5 CH(OH)CN. When treated with emulsin it yields hydro- 
gen cyanide, benzaldehyde, and glucose. 

The isolation of jS-methylsesculetin would indicate that the bark con- 
tained a small quantity of the glucoside methylffisculin. 

Amygdalin, C20H27O11N, melts 200° and when treated with emulsin 
yields hydrogen cyanide, benzaldehyde, and two molecules of dextrose. 

Sambunigrin and prulauresin, isomeric with Z-mandelonitrile gluco- 
side, melt and have specific rotation respectively 151° (a) D — 76° and 122° 
(a) D — 52.75°. The former hydrolyses to dextrose and Z-mandelonitrile 
and the latter to dextrose and d-Z-mandelonitrile. 



344 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The detection of wild-cherry bark in medicinal preparations is usually 
accomplished by setting free and isolating the hydrogen cyanide and by 
noting the fluorescence of an extract of the sample due to the methyl 
aesculin. These tests are not conclusive, but at present they take us as 
far as we can go. It is not possible to isolate the characteristic glucoside 
from the amount of material which the analyst ordinarily has at his 
disposal. 

The hydrogen cyanide can be isolated both qualitatively and quan- 
titatively by exhausting the sample with hot alcohol, removing the solvent 
by evaporation over the steam-bath, transferring the residue with 50 mils 
water to a distilling flask fitted for steam distillation, adding 10 mils of 
dilute hydrochloric or sulphuric acid and distilling, keeping the water 
volume fairly constant until the distillate gives no further test for hydro- 
gen cyanide. To determine the quantity of this substance the dis- 
tillate should be treated with an excess of sodium bicarbonate and then 
titrated with iodine to the appearance of a yellow color. 



Cherry-laurel Water 

Cherry-laurel water is prepared by aqueous distillation of the fresh 
leaves of Prunus lauro-cerasus. The finished product is often employed 
in Europe as a sedative narcotic but has never been used to any extent 
as a drug in this country. The distillate contains the essential oil of the 
leaf, benzaldehyde, and hydrogen cyanide, but the two latter gradually 
establish an equilibrium, and the liquid then contains hydrogen cyanide 
and benzaldehyde cyanohydrin. 

HCN+C 6 H 5 CHO < > C 6 H 5 CH(OH) ■ CN 

The rapidity with which the final condition of equilibrium is attained 
depends on whether the solution is more or less acid. 

The product is an unsatisfactory preparation at best and the cyano- 
genetic substances are variable. If assayed according to the official method 
for hydrocyanic acid, the determination should be made as soon as the 
product is distilled, otherwise the results will not show the total quantity 
of cyanide bodies present. 

A distillate from bitter almonds, known as bitter almond water, is 
prepared in the same way as cherry-laurel water and consists of the same 
or closely related ingredients. It has been largely replaced by benzal- 
dehyde water. 

Power and Moore ! examined the leaves of Padus virginiana and found 
present £-mandelonitrile glucoside, the same substance present in the bark, 
1 Trans. Chem. Soc, 1910, 97, 1099. 






GLUCOSIDES 345 

and also an enzyme which hydrolyzes /3-glucosides. It is not unlikely that 
these or similar substances, possibly the racemic form of the glucosides, 
are present in the leaves of Prunus lauro-cerasus and give rise to the prod- 
ucts of hydrolysis found in the distillate. 

Hydrocyanic Acid, HCN 

Hydrocyanic acid is used in medicine for alleviating spasmodic con- 
ditions, nervous coughing, whooping cough, vomiting, colic, angina pec- 
toris and cholera. Locally it is applied to the unbroken skin to allay 
itching. It is, of course, used in very weak solutions and the pharmaco- 
copceial acid is of 2 per cent strength. It is one of the constituents of 
chlorodyne and other mixtures of this type, being combined with morphin, 
Cannabis indica, and chloroform. 

It is of still further interest to the drug chemist as it occurs as benzal- 
dehyde cyanhydrin in a number of pharmaceutical preparations which 
are made from vegetable products containing amygdalin, and possibly 
other glucosides of similar nature. Thus it is a constant component of 
Cherry-laurel water or Kirschwasser, an anodyne and antispasmodic remedy 
distilled from the leaves of the cherry laurel (Prunus laurocerasus), and 
in natural oil of bitter almonds, and in bitter almond water. 

The pure acid is a clear colorless liquid with an unmistakable odor, 
boiling 26.5° and solidifying at —15°. It is soluble in water, alcohol, 
and ether. Its vapor burns in the air with a violet-blue flame, forming 
carbon dioxide, nitrogen, and water. It is a weak acid and only tempor- 
arily reddens litmus. It is known practically only in dilute solutions 
which are very poisonous. 

Hydrogen peroxide changes it to oxamide. Silver nitrate produces 
a voluminous precipitate which is insoluble in dilute nitric acid but will 
dissolve in concentrated acid. Silver cyanide when boiled with hydro- 
chloric acid reacts and the odor of hydrocyanic acid is apparent. 

Hydrocyanic acid may be detected in dilute solutions by adding a few 
drops of potassium nitrite solution followed by a few drops of ferrous sul- 
phate and enough dilute sulphuric acid to cause the yellow-brown color 
of the basic ferric salt to become yellow. The liquid is then boiled, cooled, 
the excess of iron precipitated with ammonia and filtered. A few drops 
of freshly prepared ammonium sulphide are then added and a violet color 
will appear, changing through blue and green to a yellow color. 

An alkaline solution of hydrocyanic acid or a cyanide on treatment 
with ferrous sulphate and hydrogen peroxide, followed by an excess of 
hydrochloric acid will give a precipitate of Prussian blue. 

Hydrocyanic acid can be estimated in dilute solution or in the almond 
and cherry waters by weighing out a sample, adding a slight excess of 



346 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

magnesium oxide and a few drops of potassium chromate and then titrat- 
ing with silver nitrate until a brownish-red color is obtained. 

1 mil N/10 AgN0 3 = . 002702 gm. HCN 

The cyanides of mercury and potassium are used to some extent 
medicinally. The former often replaces mercuric chloride as an anti- 
septic, and the latter is a sedative and anodyne. 

Hydrogen peroxide is one of the accredited antidotes in cases of cyanide 
poisoning, hence it should be looked for in any mixture advertised for 
this purpose. 

Oil of Bitter Almond 

Oil of bitter almond is obtained by macerating the kernels of Prunus 
amygdalus or of Prunus armenicaca (apricot) with water and distilling. 
The commercial oil contains a small quantity of hydrogen cyanide and 
cyanogenetic products (benzaldehyde-cyanhydrin). When freshly dis- 
tilled it is a colorless liquid, but as it ages it becomes yellow. Its use in 
medicine is limited. It may be expected in nerve sedatives and cough 
remedies and to allay severe itching. It is also used as a flavoring agent 
and to conceal the taste of cod liver and castor oils. For all practical 
purposes the artificial benzaldehyde answers all the requirements of the 
distilled oil and when pure is much less poisonous. 

In order to test for hydrogen cyanide 10-15 drops of the oil are shaken 
with 2-3 drops of a strong solution of sodium hydroxide. Several drops 
of ferrous sulphate containing some ferric salt or a little hydrogen per- 
oxide are added and the mixture shaken and acidulated with hydrochloric 
acid. Upon solution of the iron salts a precipitate of Prussian blue results 
if hydrogen cyanide is present. 

Nitrobenzol is sometimes used as an adulterant and may be detected 
by dissolving the oil in twenty times its volume of alcohol, adding water 
until turbidity results, and then introducing zinc and sulphuric acid to 
generate a slow stream of hydrogen. After several hours the solution 
is filtered, the alcohol evaporated, and the residual solution boiled with 
a drop of potassium bichromate which will cause the development of a 
violet color. 

The presence of non-aldehydic constituents may be detected by shak- 
ing 5 grams of the sample with 45 grams of saturated sodium bisulphite 
solution and then adding water and warming, whereupon non-aldehydic 
substances will rise to the surface. 

Artificial benzaldehyde is considered an adulterant of this oil and its 
presence was formerly considered as established if chlorine could be 
detected. There are many reasons why this is a very doubtful criterion 
as to the presence of artificial benzaldehyde, and at the present time an 



GLUCOSIDES 347 

analyst should draw no definite conclusions on the subject unless he has 
more substantial proof of the sophistication. 

Probably the simplest method of detecting the presence of chlorine 
products would be to boil the suspected sample under a reflux with alco- 
holic potash, evaporate the alcohol, take up with water and remove the 
oily constituents with ether, precipitate the aqueous liquid with silver 
nitrate in presence of nitric acid, and identify the silver precipitate as 
the chloride in the presence of cyanide. 

Free hydrogen cyanide is determined according to the method described 
under hydrogen cyanide. Applied to the oil, 1 gram of the sample is care- 
fully weighed into a small Erlenmeyer flask, and 10 mils of a mixture of 
freshly prepared magnesium hydroxide and several drops of potassium 
chromate added. The mixture is then titrated with N/10 silver nitrate 
until the formation of red silver chromate. 

The total cyanogen etic constituents are determined by saponifying a 
weighed sample with alcoholic potash, diluting with water, filtering if 
necessary, and precipitating with silver nitrate in the presence of nitric 
acid. After the liquid has become clear the silver cyanide is collected on 
a tared Gooch, washed with water and dried at 100°. The silver pre- 
cipitate obtained in this way represents all of the hydrogen cyanide, 
free and combined, and with the figures of both determinations the rela- 
tive amounts of each are a simple matter of calculation, 

GLUCOSIDES OF THE MUSTARD SEED 

Sinalbin, C30H42O15N2S2 • 5H 2 0. 
Sinigrin, CioHi 6 9 NS 2 K 

Mustard seed is the ripe seed of Sinapis alba L. (White mustard), 
(Cruciferse) , Brassica niger L. (Black mustard), Brassica junicea, or 
the varieties or closely related species of the type of B. nigra and B. junicea. 

Sinalbin occurs in the white mustard seed and sinigrin in the black. 
In addition to these glucosides, sinapin, C16H23O5N, an alkaloid, occurs 
in both varieties of seeds. Another important constituent is an enzyme, 
myrosin, which readily hydrolyzes the glucosides when the seeds are 
powdered and digested with water at the ordinary temperature. 

Black mustard seed deprived of its fixed oil is used in the manufacture 
of mustard plasters. As a household remedy, commercial ground mus- 
tard, which is usually prepared from both white and black seeds, is used 
in poultices, as an emetic and for relieving obstinate hiccough. 

Sinalbin 

Sinalbin forms yellowish needles, melting anhydrous at 138-140°, 
slightly soluble in cold water and alcohol, readily in hot water and insol- 



348 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

uble in ether. Its aqueous solution is alkaline, bitter, and gives a yellow 
color with alkalies. 

On hydrolysis by myrosin, it yields dextrose, sinalbin, mustard oil 
(p-hydroxybenzylisothiocyanate), and sinapin hydrogen sulphate. 

C30H42O15N2S2+H2O = C6H12O6+C7H7O • NCS+C16H24O5N • H2SO4 

Sinigrin 

Sinigrin is potassium myronate. It crystallizes in colorless needles, 
melting 126-130°, soluble in water, somewhat soluble in warm methyl 
alcohol, sparingly in cold alcohol, insoluble in ether, chloroform, and 
acetone. It is converted by myrosin to dextrose, allyl isothiocyanate, and 
potassium bisulphate. 

CioHi 6 9 NS2K-f-H 2 = C 6 H 12 06+C3H5NCS+KHS04 

Allyl isothiocyanate is commonly known as mustard oil, and is a vola- 
tile liquid with a pungent odor and taste. The sinalbin mustard oil is 
not volatile. 

Sinigrin gives a white precipitate with basic lead acetate in presence 
of ammonia. 

Sinapin 

Sinapin is not known in the free state, as it decomposes into cholin and 
sinapic acid when solutions containing it are evaporated. It exists as the 
thiocyanate in the seeds and is one of the products of hydrolysis of sinal- 
bin. Aqueous solutions of the free base are alkaline and have a yellow 
color. 

Sinapin may be separated from the thiocyanate by treating the solu- 
tion with silver sulphate, separating the silver precipitate, removing the 
sulphate with barium hydroxide, leaving the free alkaloid. 

Sinapic acid, C11H12O5, one of its products of decomposition, crystal- 
lizes from alcohol in prisms, melting 191-192°. 

The percentage of allyl isocyanate in mustard seed is ascertained by 
the method described on page 51. 

Bitter Tonic Drugs 
GENTIOPICRIN AND THE GENTIAN GLUCOSIDES 

Gentiopicrin occurs in the root and other parts of the anatomy of 
several of the Gentianacese. The rhizome and roots of Gentiana lutea 
furnish the official drug, gentian, which has attained wide popularity as 
a bitter tonic and which enters into the composition of a variety of for- 



GLUCOSIDES 349 

mulas. The plant grows among the Apennines, the Alps, the Pyrenees, 
and in other mountainous or elevated regions of Europe. Several of the 
species are credited with analogous medicinal properties, and their roots 
are either mixed with the official drug or are used locally for the same pur- 
poses. G. lutea requires several years to reach maturity, but the root 
is gathered at any period during the growth of the plant. 

The rhizome and roots of G. elliotii, syn., Dasystephana parvifolia, 
indigenous to the southeastern part of this country, were at one time 
official. 

Liquid extracts of gentian are usually flavored with bitter orange peel, 
cardamon, or lemon peel. Of the numerous types of pill and tablet 
formulas containing extract of gentian may be mentioned those in which 
it is combined with Podophyllum, colocynth, Hyoscyamus, Cascara 
sagrada, Juglans, Nux Vomica and Apocynum; with strychnin, ipecac, 
black pepper, and oil of cloves; with quinidin, cinchonidin, Althea, and 
hydrochloric acid (Catarrh formula) ; with colocynth, jalap, Podophyllum, 
leptandra, Hyoscyamus and oil of peppermint (cathartic compound); 
with cinchonidin, cardamom, pimento, ginger, pepsin, and hydrochloric 
acid; with aloes, rhubarb, and caraway; with ipecac, opium, mercury, 
and chalk; with quinin, arsenic, and atropin; with strychnin, ipecac, 
Capsicum, rhubarb, and sodium bicarbonate; with Nux Vomica, Ignatia, 
Cinchona, Calumba, German chamomile, phosphorus, and aromatic 
powder; with quinin, strychnin, arsenous acid, and reduced iron; with 
quassia; in Warburg's tincture, which is dispensed in the liquid, capsule, 
pill, and tablet form, where it occurs with rhubarb, angelica seed, Inula, 
saffron, fennel, zedoary, cubeb, myrrh, white agaric, camphor, quinin, 
or cinchonin and cinchonidin, with and without aloes. 

Elixirs of gentian alone and with other well-known bitters such as 
colocynth and quassia, will often be encountered, as well as more complex 
mixtures containing Taraxacum, Yerba Santa, licorice, wild cherry, and 
Eucalyptus; with iron citrochloride or pyrophosphate with or without 
pepsin. 

Adulteration with Rumex alpinus has been reported. The root of Fra- 
sera carolinensis, American calomba or yellow gentian, which grows in 
the Eastern United States and Canada, resembles in the whole condition 
the official gentian, but is lighter in color. It contains gentiopicrin. 

The fresh root contains the glucosides, gentiopicrin, and gentiamarin, 
and possibly a third known as gentiin, and a carefully prepared dialyzed 
extract of the fresh root in 60 per cent alcohol contains them in an unaltered 
condition. As the root is ordinarily dried for the market these glucosides 
are broken down, due to the action of emulsin, and as they are also hydro- 
lyzed even in the presence of alcohol, ordinary medicinal preparations 
contain only their decomposition products. This action seems to impair 



350 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

but little the bitter effect of the drug, and the therapeutic significance 
of the undecomposed glucosides has not yet been determined, though 
their decomposition is detrimental to the identification of the drug by 
chemical means. 

The glucosides are not precipitated by lead subacetate, and they may 
be separated from the root or a drug extract by extracting with alcohol. 

If carefully dried under cover, gentian will lose but a small quantity 
of gentiopicrin, and the marketable drug may then contain from 5-6 per 
cent, the loss ordinarily sustained is due to fermentation previous to or 
during drying. Tinctures made by macerating for a long period with 
60 per cent alcohol lose practically all the gentiopicrin, but if the powdered 
root is heated to boiling with 60 per cent alcohol for twenty minutes and 
then cooled and macerated, the tincture will contain the glucosides. 

The fresh gentian root contains the glucosides above mentioned, gen- 
tisin, quercitrin or an allied product, saccharose and possibly other sugars, 
pectin and other substances not yet studied. Unless carefully dried the 
saccharose is changed during the process of curing. 

Gentiopicrin 

Gentiopicrin crystallizes in two forms, anhydrous, C10H20O9, and 
hydrated, CioEboOg-f-iBkO; the former, melting 191°, is obtained from 
absolute alcohol or anhydrous ethyl acetate; the latter, melting 122°, 
from water or hydrated ethyl acetate, it is dehydrated at 105°. It has 
a lactone structure and forms gentiopicrinates with alkalies. Hydrated 
gentiopicrin has (a) d— 198.75. It forms a pentacetyl derivative, melting 
139°. It is slightly soluble in ether and is removed from acid solutions 
to a slight extent by that solvent. On hydrolysis by emulsin or dilute 
sulphuric acid it yields gentiogenin, which is insoluble in 60 per cent 
alcohol. 

Gentiogenin gives a characteristic reaction with concentrated sulphuric 
acid. If dissolved in 3-4 mils of 95 per cent alcohol and an equal volume 
of acid added without mixing, a blue zone appears at the point of contact. 
If dissolved in the acid the solution is brown, and adding water drop by 
drop the blue color develops. 

Gentiamarin, Ci 6 H2 Oio or Ci 6 H 2 20io 

Gentiamarin is amorphous and bitter, (a) D — 80° or —90°, the higher 
value being due to traces of gentiopicrin. When hydrolyzed with sul- 
phuric acid it gives an amorphous brown substance which is not gentio- 
genin, as it does not give a blue color with sulphuric acid. It does not 
possess a lactone structure nor does it combine with alkalies nor yield an 
acetyl derivative. 



GLUCOSIDES 351 



Gentiin 



Gentiin crystallizes from 60 per cent alcohol in pale yellow microscopic 
needles, melting 274°; slightly soluble in water and gives a blackish-green 
color with ferric chloride. It has no lactone structure. With nitric acid 
a green solution is obtained, changing to orange on the addition of alkali. 
When hydrolyzed in a sealed tube with dilute sulphuric acid, glucose and 
xylose are formed, together with a yellow, crystalline substance, C14H10O5, 
melting 225°, and subhming 195°. 

The identification of extract of gentian root in medicines, unless present 
in large quantity, is not easy of accomplishment because of the instability 
of the active principles. The separatioa and identification of gentiopicrin 
and gentiamarin may be accomplished by following Tanret's procedure 
which is also a quantitative method for a proximate assay of the root. 
The details are as follows: 

An alcoholic extract of the drug or of a medicinal mixture is freed of 
its alcohol and dissolved in water. It is then extracted several times 
with ethyl acetate saturated with water, the combined solvents filtered, 
concentrated, and allowed to stand, when a syrupy deposit will be obtained. 
This deposit contains the gentiopicrin and gentiamarin with a little gentiin, 
the greater portion of the latter remaining behind in the ethyl acetate. 

The syrupy mixture is then dissolved in an equal weight of boiling 
absolute alcohol, and on cooling impure gentiopicrin will crystallize. By 
repeated crystallization from ethyl acetate containing 2 per cent water, 
the more soluble gentiin will be eliminated and pure gentiopicrin obtained. 
The alcoholic mother liquor from which the impure gentiopicrin first 
crystallized is evaporated to a syrup, extracted with ether and chloroform, 
then dissolved in water, and precipitated with a 20 per cent solution of 
tannin. After filtering, the solution is treated with a large excess of tannin 
and the glucosidal tannate salted out in the cold with magnesium sul- 
phate, and then extracted with 80 per cent alcohol. The alcoholic solu- 
tion is shaken with hydrated lead oxide, filtered, the excess of lead removed 
and the filtered alcoholic solution concentrated in vacuo, the residue con- 
sisting of gentiamarin. 

The gentiin remaining in the ethyl acetate is recovered by evaporating 
the solvent and crystallizing the glucoside from 60 per cent alcohol. 

Chirata 

Swertia chirata (Gentianaceae) is a simple bitter tonic having a limited 
medicinal use. The entire herb constitutes the drug. 

Chirata is sometimes combined with iron, Euonymus, Podophyllum 
resin, Veronica, and creosote. 

The chemistiy of this drug has been imperfectly determined, but it 



352 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

contains one or more bitter principles which are probably related to those 
occurring in other drugs of the Gentianacese. The presence of ophelic 
acid, C13H20O10, and chiratin have been reported. The latter is described 
as a yellow hygroscopic powder, sparingly soluble in cold water, but readily 
in hot water, alcohol, and ether, with a neutral reaction, and giving a 
heavy precipitate with tannic acid. On hydrolysis it yields ophelic acid 
and a bitter substance. 

Chirata is a native of India, where its medicinal virtues have been 
held in high repute for a long time. The name has been applied to many 
other bitter drugs sold in India and some of these false chiratas have 
reached our markets. 

Elaterium and Elaterin 

The juice of the fruit of Ecballium elaterium (Cucurbitaceae) yields 
a sediment to which the name elaterium has been given. This product, 
which has powerful purgative properties, contains about 30 per cent of 
commercial elaterin, which is resolvable into two isomeric principles, a- and 
/3-elaterin. a-elaterin constitutes from 60-80 per cent of commercial 
elaterin and is devoid of purgative action, the physiological property of 
the drug being due to the /3-compound. Elaterin occurs as such in the 
fresh juice and is not in glucosidic combination. 

Both elaterium and commercial elaterin are employed as medicinal 
agents and are dispensed chiefly in the form of pills and tablets of small 
grainage. On account of their powerful action neither the drug nor its 
active principle are sold as popular remedies, but are prescribed in the 
treatment of dropsy. 

The crude drug varies greatly in its strength, due to amount of elaterin 
present. It occurs in light, friable, flat, or slightly curved opaque cakes 
about to in. thick, of a greenish-gray color, becoming yellowish by ex- 
posure, with a faint tea-like odor, and a bitter, somewhat acrid taste. It 
is inflammable and so light that it swims when thrown upon water. In- 
ferior specimens are paler in color without any green tint, soft and friable, 
and usually sink in water. The best grades come from England, where 
the plant is cultivated and the elaterium prepared as a regular industry. 
About 6 per cent of the drug is soluble in water. A small quantity of 
starch is present in authentic specimens. 

Alcohol and chloroform extract a dark-green resin. The resin dis- 
solves freely in ether and may be thus readily separated from the elaterin, 
which is only sparingly soluble. The elaterin of the pharmacopoeias is 
a nearly colorless, tasteless, crystalline powder, melting and decomposing 
at 217-220°, sparingly soluble in ether and alcohol, readily in chloroform, 
and precipitated from its solution in the latter by the addition of ether. 

Elaterin is soluble in alkalies and is precipitated by acids. It may 



MM 



GLUCOSIDES 353 

be removed from acid aqueous mixtures by ether, but more readily by 
chloroform. 

Elaterin and elaterin residues give with concentrated sulphuric acid, 
a pink color, quickly changing to reddish-yellow; with Froehde's reagent 
a pink to yellowish-green to deep green; with ammonium vanadate in 
sulphuric acid, an intense blue, soon fading to dirty yellow, undissolved 
crystals becoming orange and finally deep green, which is a very character- 
istic reaction. 

Power and Moore x by fractionally crystallizing commercial elaterin 
from absolute alcohol, have separated two isomeric substances to which 
they give the names a- and /3-elaterin. 

r"~ a-elaterin, C28H3SO7, forms hexagonal prisms, melting 230° C, very 
sparingly soluble in absolute alcohol, (a) D — 52.9° in chloroform. The 
molecule contains an acetyl, a lactone, and two phenolic groups. When 
oxidized with chromic acid it yields a ketone elaterone, C24H30O5, crys- 
tallizing from alcohol in needles, melting 300°, (a) D + 120.5° in chloro- 
form. 

/3-elaterin has apparently the same empirical composition and crys- 
tallizes in plates which are readily soluble in absolute alcohol. It melts 
190-195°, (a)z>+13.9°. It is to this body that the purgative value of 
elaterin and the drug is due. 

Power and Moore conclude that the only means of arriving at the 
physiological value of the drug would be to adopt definite limits for its 
specific optical rotation. The dosage of a product conforming to such a 
standard could then be adjusted in accordance with the results obtained 
by physiological or chemical tests. 

Colocynth 

The pulp of the dried, peeled fruit of Citrullus colocynthus (Cucur- 
bitacese) is the official drug colocynth. It is a powerful hepatic stimulant 
and hydragogue cathartic and has an extended use in medicine, being 
usually combined with other cathartics and dispensed in the form of pills 
and tablets. The well-known colocynth comp. pills consist of colocynth, 
aloes, scammony, and oil of cloves, and when made according to the 
British formula contain potassium sulphate in addition. The U. S. P. 
vegetable cathartic pills consist of colocynth comp., Hyoscyamus, jalap, 
leptandra, Podophyllum, and oil of peppermint. Colocynth comp. is 
present in several types of mixtures with Hyoscyamus, e.g., with Hyos- 
cyamus and mercury mass, with podophyllum, with calomel and gentian, 
with rhubarb and oil caraway, with aloes and tartar emetic, with Nux 
Vomica, with jalap, Podophyllum and capsicum; with calomel and Podo- 

1 Pharm. J., 1909. 



354 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

phyllum; and with calomel and Colchicum. Formulas similar to the 
U. S. P. cathartic compound also may contain gentian, gamboge, soap, 
cardamon, ginger, rhubarb, leptandra, and ipecac. Colocynth compound 
occurs with Cinchona alkaloids, oleoresin pepper and ferrous sulphate; 
strychnin, belladonna, ipecac, and mercury mass; rhubarb, aloes and 
mercury mass; with calomel; with mercury mass alone, and with ipecac; 
with Podophyllum; with Podophyllum and calomel; with Podophyllum, 
calomel, belladonna, ipecac, Nux Vomica, and oil of anise; with Podo- 
phyllum, aloin, Nux Vomica, Capsicum, and croton oil; with inspissated 
ox gall, pancreatin, quinin, Nux Vomica, and Taraxacum; with quinin. 
Colchicum, Hyoscyamus, opium, and mercury mass. 

Powdered colocynth or its extract is combined with aloes, gamboge, 
soap, and anise; with Podophyllum, Hyoscyamus, Cascara sagrada, jug- 
lans, Nux vomica, gentian, and Apocynum cannabinum, and in other 
formulas of the same general character as those above described, but in 
most products colocynth is added as the extract of colocynth comp., 
and if the formula is given, the grainage is usually expressed in terms of 
the latter compound and not as colocynth extract alone. 

The presence of seeds in the powdered drug is indicated by the appear- 
ance of numerous albuminous granules derived from the cotyledons. If 
the powder is placed on a glass slide, with a drop of water and a cover 
glass rubbed over it, fragments of the double-walled embryo sac show 
on the outer side elongated, more or less hexagonal, thin-walled cells, and 
on the inner side irregular, tabular, thick-walled cells. An amount of 
fixed oil in excess of 2 per cent, determined by petroleum ether extraction 
is further indication of the presence of seeds. The ash of colocynth pulp 
may run from 7.2-13.5 per cent. 

Power and Moore x found that the active principles of colocynth are 
a weak alkaloid and a non-basic indeterminate substance in the resin. 
The alkaloid has an extremely bitter taste, is soluble in water and dilute 
acids and precipitated by the ordinary alkaloidal reagents, tannin and 
basic lead acetate. It is soluble in chloroform, but not to any extent in 
ether. It is removed from its chloroformic solution by hydrochloric acid. 
The resin is only partly soluble in alcohol, the insoluble portion contain- 
ing a-elaterin, melting 232°, sparingly soluble in ether, and less so in 
alcohol and water, but readily in chloroform. The alcoholic soluble 
portions contain non-glucosidic substances of a purgative nature. 

Power and Moore also isolated from the pulp a new phytosterol gluco- 
side to which the name citrullol was given. This substance is soluble in 
water, from which it may be removed by repeated extraction with ether. 
On crystallization from pyridin it melts 285-290°. When dissolved in 
chloroform with a little acetic anhydride, the addition of concentrated 
1 Trans. Chem. Soc, 1910, 99. 



GLUCOSIDES 355 

sulphuric acid will produce a series of color reactions similar to those 
given by the phytosterols. This same substance has been isolated from 
the drug Euonymus atropurpureus. 

The seeds contain a trace of the same alkaloid but no a-elaterin. No 
evidence could be obtained of the presence in colocynth of /3-elaterin, 
which constitutes the physiologically active constituent of the fruit of 
Ecballium elaterium. 

As a result of this investigation it would appear that the so-called 
" colocynthin " of previous investigators is a mixture of citrullol and the 
alkaloidal principle. 

■When manipulating colocynth extracts in solution according to the 
scheme of analysis for obtaining qualitative reactions, an extract will be 
obtained by shaking out the acid solution with ether, which will give a 
yellow -brown color with concentrated sulphuric acid, a dirty-red to cherry- 
red with Froehde's reagent, and a red, also pink to deep crimson with 
ammonium vanadate and the first color obtained in the last test will 
show blue in thin layers. 

The basic or alkaloidal constituent of colocynth is of little value as 
an aid in detecting colocynth in mixtures on account of the small quantity 
occurring in the drug, and because its chemical properties are not well 
defined. If a sufficient quantity can be extracted and its purgative action 
tested on animals, a strong positive indication of the presence of colo- 
cynth would be established. But as colocynth is dispensed to such a 
large extent with Hyoscyamus, the mydriatic alkaloids will almost com- 
pletely mask the colocynth bases. 

The analyst will be obliged to depend upon the isolation of intensely 
bitter residues by an ether extraction of an acidulated aqueous extract 
of the alcohol soluble portion of the medicine under examination, and 
to diagnose the presence of colocynth by a careful observation of the 
color reactions performed on these residues. On rendering the acid solu- 
tion alkaline the alkaloidal constituent is removed by agitation with 
chloroform. 

The alcoholic soluble portion of the medicine, after washing with wateT 
to obtain the above-mentioned solution, will probably be a resinous mass 
which on careful treatment with absolute alcohol may leave a small por- 
tion of a-elaterin undissolved, and which on crystallization from absolute 
ether may be identified by its melting-point. This evidence is not neces- 
sarily conclusive of the presence of colocynth, because the absence of 
j8-elaterin should be established, otherwise it may transpire that com- 
mercial elaterin, or Elaterium, is present in the mixture. 

That portion of the resin soluble in absolute alcohol will be found to 
have a purgative action if submitted to a physiological test, but this 
evidence is of no value in establishing the presence of colocynth in mix- 



356 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

tures, because the purgative principles of scammony and some of the other 
cathartic drugs which usually accompany colocynth reside in resins which 
will appear at this point and are soluble to a greater or lesser extent in 
alcohol. 

Colocynth extracts are not precipitated by iron salts, neither do they 
give any color reactions with the same reagent because no tannins are pres- 
ent, and the drug is one of a very few that does not contain some tannin- 
reacting substance. 

Quassia 

The wood of Picrsena excelsa (Simarubese) contains a bitter substance 
or group of substances to which the name quassia is given. The drug 
is a bitter tonic and is employed in cases of impaired digestion 
to tone up the stomach, and is usually combined with iron, Nux Vomica, 
magnesium sulphate, or gentian. The wood is sometimes turned into 
cups which can be rilled with water and the liquid imbibed for its bitter 
and tonic action. Strips of porous paper saturated with quassia syrup 
are used for fly poisons. 

The drug appears to have been obtained from two plants of the same 
genus, the original quassia coming from Quassia amara (Picrsena amara), 
a small branching tree or shrub of Surinam, West Indies, northern South 
America, and some tropical parts of the Old World. The P. excelsa, which 
supplies the present commercial drug, is a large forest tree native of 
Jamaica and the Caribbean Islands. 

Quassia occurs in cylindrical billets of various sizes and lengths, fre- 
quently accompanied with a light-colored sweetish, slightly adherent and 
bitter bark. Again it will be found in splinters or chips. 

Quassin is apparently a composite substance, analogous in this respect 
to commercial elaterin. It crystallizes in oblique rhomboidal needles with 
a pearly luster. It is odorless, but has a bitter taste. Its melting-point 
is 210° C. and on cooling it forms an amorphous mass. It is soluble in 
about 400 parts of water at 15° C; in 30 parts alcohol (85 per cent) and 
in 21 parts of cold chloroform. It is very soluble in boiling alcohol, in 
acetic acid, and very slightly soluble in ethyl and petroleum ethers. It is 
soluble in concentrated acids and alkalies, but not in alkaline carbonates. 
Continued action of alkalies forms resins. It is dextrorotatory in its 
chloroform solution; 4.22 gm. in 100 mils chloroform rotating the plane of 
polarized light to the right with a specific rotation of plus 38° 8'. Solu- 
tions of quassin are neutral. 

It dissolves to a colorless solution in concentrated sulphuric acid, which 
becomes red on the addition of sugar. 

It is precipitated by tannin from aqueous solution, but not by neutral 
or basic lead acetate, iodine, iron, or potassium mercuric iodide. 



GLUCOSIDES 357 

Quassin may be removed from an aqueous acid solution by chloroform 
and the residue left on evaporating the solvent subjected to the color 
test with sulphuric acid and sugar. Concentrated sulphuric acid alone 
produces no color. 

Allen has suggested a reaction with bromin water, which is of value 
in identifying quassin and in detecting it in presence of other bitters. 
The residue is dissolved in chloroform and shaken with an excess of bromin 
water, the chloroform solution separated and shaken with ammonia. The 
color due to bromin will immediately disappear and if quassin be absent 
both the solvent and ammonia will be colorless, but in presence of quassin 
the chloroform will be colored bright j T ellow. 

Quassin has been separated into two components, a- and /3-picrasmin. 
The alcoholic extract is neutralized with magnesia, then acidified with 
tartaric acid, and the alcohol distilled off. The residue is shaken up with 
chloroform and the solution evaporated to syrupy consistency and dis- 
solved in a mixture of equal parts of absolute alcohol and ether. This 
solution is evaporated and the residue dissolved in as little absolute alcohol 
as possible, the solution covered with a layer of ether and allowed to 
evaporate. The crystals which form are recrystallized from alcohol. The 
product thus prepared consists of two bitter principles, a-picrasmin 
(C35H48O10), melting at 204° C, and /3-picrasmin (C36H48O10), melting at 
209-212° C. 

Simaruba Bark 

The bark of the root of Simaruba officinalis was formerly recognized 
in the Pharmacopoeia. The plant is a large tree closely allied to the 
quassia, and the drug contains a bitter principle which may be related 
to quassin. The bark contains a fixed oil, resinous material, a crystal- 
line bitter substance, a crystalline non-bitter substance, gallic acid and 
a fluorescent principle. The tree grows well in Jamaica. S. amara is 
indigenous to Brazil and Guiana and S. glauca to the West Indies and 
Central America. 

Simaruba has a limited use as a bitter tonic and in solution might 
readily be mistaken for quassia except that it contains gallic acid, which 
gives a precipitate with iron salts. However, this difference is of little 
importance analytically as the bark of quassia may be admixed with the 
wood of the official drug and it is not unlikely that gallic or tannic acid 
would be present in the bark. 

Juglans. Butternut root-bark 

The root-bark of Juglans cineraria (Juglandacese) has a mild cathartic 
and tonic action and is often present in mixtures intended to relieve con- 
stipation and biliousness. As a general thing it is mixed with Podo- 



358 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

phyllum resin, colocynth, Hyoscyamus, Cascara sagrada, Nux Vomica, 
gentian, Apocynum, senna, and Rochelle salt in some combination or 
other, and certain special types of preparations contain the extract of 
butternut with manganese iodide, Sanguinaria, Hyoscyamus, and Veronica 
virginica; and with Podophyllum resin, Cimicifuga, Veronica virginica, 
and Capsicum. 

A concentrated extract of the drug consisting chiefly of the resinous 
constituents is marketed as juglandin. 

Coto 

Coto and Para coto barks are closely allied drugs of uncertain botan- 
ical origin from Bolivia and Brazil. 

Coto and its characteristic principle, cotoin, are used in diarrheic 
conditions, for cholera and rheumatism and as stomach tonics. 

Cotoin, C6H 2 (OH)2(OCH3)COC6H5, crystallizes in pale yellow lami- 
nated crystals, but it is usually marketed as a crystalline powder. It has 
a pungent taste, melts 130-131°, is sparingly soluble in cold water, more 
readily in hot water, very soluble in alcohol, chloroform, benzol, ether, 
acetone, and carbon bisulphide, but insoluble in petroleum ether. It is 
removed from its acid solution by ether. 

Cotoin crystals, when treated with concentrated sulphuric acid, turn 
orange, and the solution becomes bright yellow. Concentrated nitric 
acid produces an immediate blue color, soon changing to black and finally 
orange brown, with considerable chemical action. This is a very character- 
istic test. An aqueous solution of cotoin is colored violet brown by ferric 
chloride. 

Para Coto 

Para coto is used like coto as an appetizer and for diarrhea, dysentery, 
and similar disorders. 

The chief constituent of Para coto is paracotoin, an indifferent crys- 
talline, bitter principle, hydrocotoin, methyl hydrocotoin, protocotoin, 
methyl protocotoin (oxyleucotoin), phenyl coumarin, piperonylic acid, 
volatile oil, resin, and tannin. 

Para coto is distinguished from coto by the action of nitric acid on 
the ether extractive matter. In the case of Para coto the result is the 
formation of a yellow color and in the case of coto a red color appears. 

Paracotoin, Ci 2 H 8 4 

Para coto is extracted with ether and the ether extract distilled. The 
residue is fractionated by repeated crystallizations from hot alcohol. The 
first body to separate out is paracotoin. 



GLUCOSIDES 359 

Paracotoin is a pale yellow, crystalline body, neutral in reaction, 
tasteless and odorless, melting at 149-152° C. It is difficultly soluble 
in water, but easily in ether, chloroform, and boiling alcohol. Concen- 
trated sulphuric and nitric acids dissolve it, forming a yellowish-brown 
solution. On boiling with a solution of caustic alkalies, a colorless crys- 
alline body, melting at 82-83° C. and having the odor of coumarin is 
formed; this body is acetopiperon (para-cumarhydrin) , C9H8O3 or 
C6H3O2CH2 • CO • CH3, and paracotoic acid, C12H10O5, a yellow amor- 
phous mass melting at 108° C. Paracotoin fused with potassium hydroxide 
yields principally piperonylic acid, CsHeO^ 

One gram of paracotoin shaken up with 10 mils of fuming hydro- 
bromic acid forms a semi-solid mass of yellow crystals, which on drying 
over potassium hydroxide lose hydrobromic acid. This residue decom- 
poses with water and when recrystallized forms paracotoin, recognized 
by its crystalline form and melting-point. 

By gradually adding about 1 gm. paracotoin to about 10 mils con- 
centrated nitric acid, a red-brown solution will result, which, when heated 
for a short time on the water-bath and cooled, deposits a yellow crys- 
talline mass. This product recrystallized from acetone and then from 
benzene or glacial acetic acid, forms golden-yellow crystals, melting at 
195° C. This body is dinitro paracotoin, probably of the formula 

C 12 H 6 (N0 2 )204. 

An excess of bromin added to a 10 per cent solution of paracotoin 
in choloroform cooled to 0° C. produces a deep yellow precipitate, which 
loses hydrobromic acid, and when recrystallized from alcohol forms the 
mono-bromide of paracotoin (C^HjBrO^, melting at 200-201° C. 

Fortoin is methylene dicotoin or cotoin formaldehyde. 



CHAPTER XI 
PURGATIVE DRUGS 

THE ANTHRAQUINONE DRUGS 

There are several well-known drugs which are conveniently con- 
sidered together because they all contain derivatives of anthraquinone 
and because their physiological properties are more or less alike. They 
are aloes, senna, Cascara sagrada, buckthorn, rhubarb, and chrysarobin. 
Aloes also contains certain well-defined principles known as aloins. The 
individual drugs, their properties and components will be discussed sepa- 
rately and a general discourse on their recognition in mixtures will follow. 



ALOES 

Aloes is a resinous exudation from the wounds of different species of 
the genus Aloe (family Liliacese). Commercially there are two important 
varieties, the Barbadoes and Socatrine, with others of lesser moment. 
The former, also known as Curacao aloes, is derived from A. chinensis 
and A. vera, and probably other species, and the latter, which is some- 
times termed Zanzibar aloes, comes from A. Perryi. Natal aloes, from 
an unknown source, has almost disappeared from commerce. Cape and 
Uganda aloes from Cape Colony are derived from A. ferox. Hepatic 
aloes was the name originally applied to an East Indian aloes of a reddish- 
brown or liver color, but it is now used to designate certain sorts of dark 
opaque liver-colored Socatrine aloes. 

In medicinal products both aloes and aloin are extensively employed, 
the mixtures containing them being chiefly purgatives, tonic laxatives, 
emmenagogues, restoratives, and laxative cold mixtures. They are 
usually dispensed in the form of pills and tablets. The standard liquid 
preparations, fluid aloes, contain licorice and sometimes myrrh; and the 
compound liquid aloes contains in addition to these, saffron, cardamom 
comp., and potassium carbonate. Aloes is also present in the liquid 
benzoin compounds with benzoin, storax, and tolu. 

In pill and tablet mixtures aloes will be found combined with soap; 
soap and asafetida, sometimes with confection of rose leaves; ferrous 
sulphate or Blaud's mixture with or without Nux Vomica; rose leaves and 

360 



PURGATIVE DRUGS 361 

mastic; sometimes with rhubarb (dinner pills), aromatic powder, and 
myrrh; belladonna and Nux Vomica and ipecac; iron, arsenous acid, 
and strychnin; Hyoscyamus, colocynth, and tartar emetic; rhubarb, 
ipecac, and Nux Vomica; Podophyllum resin; Capsicum and Nux Vomica; 
mercury mass, rhubarb, and colocynth; gamboge, Podophyllum, Cap- 
sicum, and croton oil; colocynth, Podophyllum, soap, scammony resin, 
and cardamom (vegetable cathartic); colocynth, scammony resin, potas- 
sium sulphate, and clove oil; ergot extract, savin oil, black hellebore, 
and ferrous sulphate, somet'mes with cotton-root bark, saffron, turpen- 
tine or pennyroyal oil in emmenagogue mixtures; cimicifuga racemosa, 
ferrous sulphate and cotton-root bark; gentian, rhubarb, and caraway; 
mercurous iodide, Podophyllum resin, Hyoscyamus and Nux Vomica; 
inspissated ox gall, stramonium, and berberin; ox gall, pepsin, ferrous 
sulphate, and Nux Vomica; sometimes with quinin; rhubarb, myrrh, 
and peppermint oil, sometimes with soap; quinin, calomel, Capsicum, 
aconite, ipecac, and opium; and others of similar composition. Aloin 
will be found in mixtures of the same general type. Some of the standard 
formulas are composed of aloin, strychnin, and belladonna, to which 
may be added Cascara sagrada, ipecac, Podophyllum resin, and ginger. 

Aloes responds to several color reactions and the same reagent often 
reacts in a different way with the different varieties, thereby furnishing 
a means of characterizing them. 

Borntrager's test consists in shaking with benzol an aqueous solu- 
tion of the drug, or an aqueous solution of an evaporated alcoholic extract, 
and after separating the benzol solution, agitating with ammonia, when, 
on standing, a pink color, varying in intensity and shade, will develop. 
This reaction is also known as the emodin test and is obtainable with all 
drugs containing anthraquinone derivatives. The pink shade is usually 
the least intense with aloes and after a little experience, the rapidity with 
which the color appears and its shade and intensity will enable the analyst 
to distinguish an aloe reaction from that of other drugs. 

Klunge's test consists in treating a very dilute aqueous solution of 
aloes with 1 drop of copper sulphate solution followed by sodium chloride 
and alcohol. The copper sulphate intensifies the yellow color and the 
salt and alcohol produce a red tint. Barbadoes and Curacoa aloes give 
a deep red, Socatrine gives various shades of red and sometimes no color, 
Natal aloes, a faint red, and the hepatic varieties usually no color. 

In Cripp's and Dymond's test a small quantity of the substance is 
triturated in a porcelain dish with 16 drops of concentrated sulphuric 
acid, 4 drops of strong nitric acid added and about 25 mils of water. A 
deep-orange to crimson color will result according to the kind of aloes pres- 
ent, and this color is intensified by adding ammonia. Barbadoes and 
Curacoa varieties give crimson colors intensified to deep claret, Natal 



362 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

deep crimson to intense brownish red; Socatrine and hepatic pale crim- 
son or orange to claret. 

Fluckiger's test, which is apparently characteristic of Natal aloes, is 
obtained by triturating with concentrated sulphuric acid and exposing 
to nitric acid vapor, when a deep-blue color will develop. Other varieties 
will sometimes give a faint blue or bluish-green color. 

Stacy x reports that a cold aqueous extract of Barbadoes aloes gives 
a pink coloration with potassium ferrocyanide. The solutions must be 
so adjusted that neither is in excess. In most cases the color appears 
after five to fifteen minutes and more rapidly on boiling. In more con- 
centrated solutions the color is deep crimson or blood red. The substance 
giving the reaction is only slightly soluble in petroleum ether, benzol, 
and chloroform, and insoluble in ether and ethyl acetate. Socatrine 
and Cape aloes and commercial aloin give a green color, while aqueous 
extract of Cascara sagrada and rhubarb do not give any reaction. The 
color yielded by Barbadoes aloes is destroyed by acids and excess of 
alkalies; small quantities of alkalies intensify the reaction, at the same 
time modifying it by the introduction of a brown tint. 

An aqueous solution of borax produces a green fluorescence with aloes 
which is visible at considerable dilution. In the U. S. P. test 1 gram of 
the drug is intimately mixed with 10 mils of water. One mil of this solu- 
tion and 100 mils of water are treated with a 20 per cent borax solution 
to obtain the reaction. Cascara gives a similar reaction, but only in a 
fairly concentrated solution. 

If an aloes residue is acidified and extracted with ether, the ether 
separated and shaken with the borax reagent, the green fluorescence will 
develop in the aqueous layer. The appearance of the fluorescence is 
often retarded, sometimes an hour will elapse before it becomes apparent. 

Aloes contain as their most characteristic constituents, aloe-emodin 
and aloin. The resinous material present yields cinnamic acid, aloe- 
emodin, and sugar upon acid hydrolysis, and p-cumaric and cinnamic 
acids on alkaline hydrolysis indicating that glucosides are present. 
Tschirch and Hoffbauer state that Curacao aloes yields only cinnamic 
acid and Zanzibar aloes only p-cumaric acids, but Tutin and Naunton 
obtained both acids from the Curasao variety. E. M. Bailey reports the 
presence of chrysophanic acid. 

The aloin of Barbadoes aloes probably has the composition C16H18O7 
(C21H20O9 or C2oHi 8 9 , Seel and Kelber) (a) D — 8.3° in 90 per cent alcohol, 
crystallizing in pale yellow prismatic needles, which are intensely bitter 
and after drying at 100° melt 145-150°, slightly soluble in cold water, 
but readily on boiling, slightly soluble in ether, chloroform, carbon bisul- 
phide, benzole, and petroleum ether, and quite easily in alcohol, acetone, 

1 Analyst, 1916. 41, 75. 



PURGATIVE DRUGS 363 

and acetic acid. It forms a tribrom-derivative melting 191-192°, which 
in turn yields a tetra-acetyl derivative melting 135°, from which it is 
assumed that barbaloin contains three hydroxy 1 groups. Its structural 
formula has not been determined with certainty. It dissolves in ammonia 
or alkalies to a deep orange-red solution with fluorescence. On adding 
ammonia and calcium chloride a precipitate is obtained. 

Alcoholic solutions of aloin are neutral to litmus. Their aqueous 
solutions are colored green or greenish-black by ferric chloride and are 
gradually precipitated by basic lead acetate. 

When boiled for twenty-four hours with an alcoholic solution of hydro- 
gen chloride it yields a trihydroxymethylanthraquinone, isomeric with 
the emodin from rhubarb and senna. 

Two isomeric barbaloins, the a and /3, have been reported, the former 
being reddened in the cold by nitric acid, and the latter only on warming 
and in this particular resembling the nataloin of Natal aloes. Nataloin 
has thus far yielded no bromo-derivative. It contains a methyl group. 
It therefore differs from the barbaloins. 

The commercial aloin is obtained chiefly from the Curacoa and Bar- 
badoes aloes. 

ALOE-EMODIN 

Aloe-emodin is an hydroxymethyldihydroxyanthraquinone, probably 
represented by the structural formula 


OH. C y CH 2 OH 

>c 6 h 2 < yc<&/ 

i 

It is closely related to chrysophanic acid which is a dihydroxymethyl- 
anthraquinone, and to emodin, which is a trihydroxymethylanthraquinone 
or hydroxy chrysophanic acid. 

Aloe-emodin crystallizes in orange-red needles melting 216-218° 
(224° Beal), sublimable, slightly soluble in water, from which it may be 
removed by immiscible solvents, and dissolving readily in alcohol, ether, 
benzol, alkalies, and glacial acetic acid. Its solution in alkalies is pink 
to deep crimson in color, depending on the quantity present. It is much 
more soluble in water when it is present with other constituents occurring 
in the drug, than in the separated and purified state. It gives a pink 
color with concentrated sulphuric acid and a pink to reddish-pink with 
Froehde's reagent. 



364 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Aloe-emodin dyes wool yellow from an acid bath, the color is stripped 
by ammonia and on acidulating the alkaline solution a second dyeing 
may be obtained. An alcoholic solution of emodin on evaporation with 
ferric chloride leaves a yellow residue; phenolphthalein under similar con- 
ditions leaves a pinkish residue with an odor of phenol, the co'or disappear- 
ing on cooling or in presence of moisture. Phenolphthalein imparts no 
color to wool. 

The presence of aloes in a medicinal preparation is usually apparent 
by the characteristic odor. If the pill or tablet is extracted with alcohol 
and the solvent evaporated, the odor of aloes will often pervade the entire 
room, and the residue will appear as a deep red varnish. This residue 
can then be submitted to the tests described above. 

Aloin alone is not detected as readily as the drug, but as the commercial 
substance often contains aloe-emodin, a weak Borntrager reaction may 
indicate the presence of aloin. As aloin is not removed to any extent 
from aqueous solution by immiscible solvents, and as it is not stable in 
the presence of alkalies it will often pass unnoticed. But if there is reason 
to suspect its presence a hot aqueous solution of the alcoholic extract 
should be filtered from any resinous matter, evaporated to dryness, 
extracted with absolute ether or chloroform to remove easily soluble 
acids, and then treated with hot alcohol and filtered from any undissolved 
sugar. On evaporation of the alcohol, the aloin will be left as a yellow 
residue and can be identified by its intense bitterness, reaction with nitric 
acid, and by the color reaction of its aqueous solution with ferric chloride, 
precipitation with bromine, slow precipitation with basic lead acetate 
after any tannins have been thrown out by neutral lead acetate, and 
precipitation of its ammoniacal solution by calcium chloride. 

In performing the iron test, if a trace of the reagent is added at first, 
a reddish-violet color is obtained, and then on adding a larger quantity 
the greenish-black color appears. If the bromine water is added drop 
by drop at half-minute intervals a violet-red color appears at first, and 
this changes to yellow after an excess has been added with the appear- 
ance of a yellow precipitate. 

Nataloin give a blue color with sulphuric acid and vapor of nitric 
acid. 

Compounds or so-called derivatives of aloin are sometimes offered 
for sale with the claim that they possess certain novelties or advantages 
over the parent drug. The well-known carbonic ether derivative is one 
of them, and by boiling aloin with a persulphate a powder is obtained 
which is claimed to have purgative properties. Formaloin is a conden- 
sation product of formaldehyde and aloin. 



PURGATIVE DRUGS 365 



RHUBARB 



The well-known drug rhubarb is the rhizome of several species of 
Rheum (Polygonaceae) . The commercial varieties are known as Chinese, 
Canton, and Shensi, and are obtained from R. officinale, R. palmatum, 
R. palmatum tanguticum, and probably others. R. raponticum yields 
the English or Austrian variety known as rhapontic rhubarb. 

Rhubarb is a popular remedy and will be found widely distributed 
in medicinal products. It has cathartic, tonic, and astringent properties, 
and is principally used in preparations designed to correct bowel and 
stomach troubles. In liquid form it is often combined with senna and 
licorice; with potassium carbonate or bicarbonate, cinnamon, Hydrastis, 
and oil of peppermint; the latter type often containing pancreatin or 
papain; aperient mixtures will contain magnesium acetate and rhubarb. 
Among the pill and tablet combinations may be mentioned those in 
which powdered rhubarb or its extract is associated with Cascara sagrada, 
Nux Vomica and aloin; ipecac, and aloes; Hyoscyamus, colocynth comp. 
and caraway; asafetida and iron; mercury mass, aloes, and colocynth 
comp.; calomel, Hyoscyamus, and colocynth comp.; alap, Jamaica gin- 
ger, colocynth conp., gamboge, and calomel; Podophyllum, Hyoscyamus, 
Capsicum, and aloes; calomel, oap, and aloes; mastic and aloes; Ignatia, 
Cinchona, and Capsicum; gentian, aloes, and caraway oil; me cury 
mass and sodium bicarbonate; myrrh, aloes, soap, and peppe mint oil; 
strychnin, ipecac, and capsicum; opiu n, ipecac, and soap; ipecac, sodium 
bicarbonate, and peppermint oil, sometimes with Cascara; magnesia; 
opium, Capsicum, camphor, and peppermint oil in Sun cholera mixture. 
Warburg tincture is composed of rhubarb, angelica seed, Inula, saffron, 
fennel, gentian, zedoary root, cubeb, myrrh, white agaric, camphor, quinin 
sulphate, or cinchonin and cinchonidin and aloes. 

The powdered drug has been found adulterated with turmeric and 
hematoxylin. 

For the detection of rhapontic rhubarb; 10 grams of the powdered 
sample are boiled for half an hour with 50 mils of dilute alcohol, filtered, 
the filtrate evaporated to 10 mils, and after cooling shaken with 15 mils 
of ether. After standing for twenty-four hours the ext act from official 
rhubarb will be clear, while that from the rhapontic variety will have 
deposited a crystalline sedmient which appears under the microscope to 
consist of neddle-like prisms. The crystalline precipitate is filtered, 
washed with water, and dried and on treatment with concentrated sul- 
phuric acid gives a purple-red color changing to orange. 

In testing for turmeric 1 gram of the powder is mixed with 1 gram of 
boric acid, moistened with 10 mils of dilute sulphuric acid and spread out 
on a porcelain plate. On drying a purple-red color develops if turmeric 
is present, but pure rhubarb give only a brown or browmsh-red shade. 



366 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The chemistry of rhubarb has been the subject of extended research. 
Tutin and Clewer * separated a small quantity of an essential oil which 
gives the drug its characteristic odor, and in the aqueous extract cinnamic 
and gallic acids, rhein, emodin, aloe-emodin, emodin monomethyl ether, 
chrysophanic acid, and rheinolic acid, a crystalline mixture of glucosides 
of the above-mentioned anthraquinone derivatives, dextrose, levulose, 
tannin, and an amorphous non-glucosidic resin which represented the 
chief purgative constituent. The resin on hydrolysis gave all of the above 
derivatives, together with a new compound, a trihydr ox yHihvHrnfln- 
thracene, C14H12O3, melting 256°. The portion of the alcoholic extract 
of the drug which was insoluble in water, when t eated with various 
alkalies, yielded a further quantity of the anthraquinone derivatives, 
several fatty acids, a hydrocarbon melting 64°, a phytosterol (verosterol), 
glucosides similar to those above mentioned and amorphorous products. 

The gallic acid present amounted to over 2 per cent, rhein 0.12 per 
cent, rheinolic acid 0.003 per cent, emodin 0.78 per cent, aloe-emodin 
0.16 per cent, emodin mono-methyl ether 0.22 per cent, chrysophanic 
acid 0.49 per cent, glucosides 2 per cent, and non-glucosidic resin 10.4 
per cent. 

The relationship of the anthraquinone derivatives is apparent from 
the following structural formulas: 

H 2 
C 

H 2 

Anthracene 



II 

c 

A. 

Anthraquinone 

o 

II 

0H \ / c \ 

>C6H2< >C 6 H4 

OH/ \/ 

il 

o 

Alizarine (Dihydroxyanthraquinone) 

1 Trans. Chem. Soc, 1911, 99, 94a 



PURGATIVE DRUGS 367 

O 
II 
OH. C /CHs 

>C 6 H 2 < 
OH/ V 



Vtffc/ N >C 6 H 3 / 



O 

Chrysophanic Acid 



II 

OH x C .CH3 

>C 6 H< >C 6 H2< 
oh/ X (/ X OH 

II 

o 

Emodin 



II 

OH. /\ y CH 3 

>C 6 H 2 < >C 6 H 2 < 
OH^ x c x x OCH 8 

II 
O 

Emodin Monomethylether 



II 

OH v A /CH 2 OH 

>C 6 H 2 < >C 6 H 3 / 
OH/ x c / 

II 
O 

Aloe-emodin 



II 

>C 6 H 2 < >C 6 H 3 -COOH 
OH/ x c / 

II 
O 

Rhein 

CHRYSOPHANIC ACID 

This substance crystallizes from ethyl acetate in deep golden-colored 
spangles melting at 191° C. (198° Beal). In the purified state it is slightly 
soluble in water and alcohol, but dissolves readily in chloroform, benzol, 



368 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

and ether. From an acidulated aqueous extract of a drug it may be 
completely removed by ether, and 5 per cent caustic alkalies extract it 
from its ethereal solution, giving rise to a beautiful purple-red liquid. 
Its diacetyl derivative melts 204°. 

Commercially, chrysophanic acid is confused with rhein, both sub- 
stances being considered identical. The same term is also applied to 
purified or oxidized chrysarobin from Goa powder, a substance deposited 
in the wood of Andira araroba. In this form it is used an as alterative 
and antiparasitic, and in ointment form is employed in psoriasis, herpes, 
and hemorrhoids. 

If a solution of chrysophanic acid in alkali is heated with a little zinc 
dust, the red color changes to yellow, due to the formation of a reduction 
product. Reoxidation takes place readily by dilution with water and 
the addition of a drop or two of hydrogen peroxide. An alkaline solu- 
tion of phenolphthalein is reduced by zinc and the color is not restored 
by peroxide. 

EMODIN 

Emodin crystallizes in deep orange needles melting 252°. Its triacetyl 
derivative melts 192° C. It is soluble in the organic solvents, and is 
removed from ether or chloroform by alkalies, forming pink solutions. 

Emodin can be separated from chrysophanic acid by dissolving a mix- 
ture of the two substances in chloroform and shaking out with sodium 
carbonate, which will remove the emodin, leaving the chrysophanic acid 
to be extracted with potassium hydroxide. 

EMODIN MONOMETHYL ETHER 

This substance melts 195° and forms a diacetyl derivative melting 
186°. It may be converted into emodin by heating to 160° with con- 
centrated sulphuric acid. 

Aloe-emodin has already been described under Aloes. 

RHEIN 

Rhein is a true acid, and is not readily soluble in the ordinary organic 
liquids, but dissolves in organic bases such as pyridin and anilin. It 
forms an orange-colored crystalline salt with pyridin which loses pyridin 
on heating to 130°. Rhein melts 318°. Its diacetyl derivative, which 
is produced on heating with a large excess of acetic anhydride in presence 
of a little camphor sulphonic acid or pyridin, melts 258°. Diacetylrhein 
may be removed from its solution in immiscible solvents with sodium 
carbonate on account of its containing a carboxyl group. When heated 
with xylene it first dissolves, then suddenly separates on boiling, and in 



PURGATIVE DRUGS 369 

this form is practically insoluble except in alkalies. Rhein dissolves in 
concentrated sulphuric acid with a red color and is precipitated on dilution. 

RHEINOLIC ACID 

Tutin and Clewer 1 separated this acid from rhein by pouring a pyridin 
solution of the two substances into ether and filtering from the precipitated 
rhein compound. The ethereal solution yielded the rheinolic acid pyridin 
compound when shaken with ammonium carbonate. On drying to 130° 
pyridin was dissipated and the free acid melted 295-297°. 

It is evidently an anthraquinone derivative. It dissolves in both 
alkalies and concentrated sulphuric acid with an intense red color, but 
differs from rhein by not being precipitated from the later solvent on 
adding water. 

Its constitutional formula has not been deteraiined. 

The chief purgative principle of rhubarb is a non-glucosidic resin 
which Tutin and Clewer found present to the amount of about 10-11 per 
cent. Of the anthraquinone derivatives only aloe-emodin and chryso- 
phanic acid have any physiological acitivity the mixture of the glucosides 
being quite inert. 

Adulteration of rhubarb with turmeric and hematoxylin can be 
detected by preparing an alcoholic extract of the product, diluted with 
water, acidified, and shaken out with ether. On transferring the ether 
solution to strips of white paper and drying, hematoxylin is indicated if 
strong hydrochloric acid produces a pink color, and turmeric if boric 
acid and dilute hydrochloric acid yield the characteristic red tint which 
is changed to blue by ammonia. 

Beal and Okey 2 subjected a dilute alcoholic extract of rhubarb to 
successive shake-outs with 4 parts of ether, benzol, and amyl alcohol. 
The benzol solution gives a violet-red precipitate with concentrated 
ammonia. The other anthraquinone drugs will give a red color in the 
aqueous layer, but rhubarb was the only one which they found yielded 
a precipitate. 

If the benzol solution is shaken with solution of lead subacetate, a 
yellow or orange precipitate is obtained which turns red with alkali. 
The precipitates of the other drugs remain white. 

When the amyl alcohol solution is shaken with lead subacetate a red 
color is obtained. In the case of tho other anthraquinone drugs no change 
takes place. 

1 Proc. Chem. Soc, 1912, 28, 13; 1913, 29, 285. 

2 J. Amer. Chem. Soc, 1917, 716. 






370 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

SENNA 

The leaves of Cassia acutifolia and C. angustifolia (Leguminosae) are 
recognized as the official drug known as senna. C. Marilandica, the 
American or wild senna, also furnishes an unofficial drug which has a 
limited use in medicine. 

C. angustifolia furnishes the Indian or Tinnevelly senna, and the 
leaves of a variety of this species growing in Arabia are known as Mecca 
or Arabian senna. The Peruvian senna is also derived from the same 
species. The Alexandrian senna comes from C. acutifolia, though by 
some authorities it is regarded simply as a variety of angustifolia. C. 
holosericia of Abyssinia is known as Aden senna. The leaves of C. obvata 
are often mixed with those of the other official species. 

The pods of the senna plants are commercially important, and are 
employed for the same purposes as the leaves. 

Senna is used in cathartic mixtures. The powdered drug is one of 
the components of compound licorice powder where it is mixed with sugar, 
sulphur, fennel, and powdered licorice root. Compound extract of senna 
contains also jalap, and coriander, and other liquid mixtures contain, in 
addition to senna, Taraxacum; Grindelia and rhubarb; Podophyllum, 
leptandra, and jalap; Spigelia, savine, and manna; rhubarb; sarsaparilla, 
licorice, sassafras, anise, and methyl salicylate, and sometimes potassium 
iodide; caraway and coriander; Cascara sagrada, leptandra, juglans, and 
tartar emetic. Tablet and pill formulas are not numerous, but are of 
the same type as those containing the other anthraquinone drugs. Pow- 
dered senna, Cascara sagrada extract, Podophyllum, and magnesia are 
components of some of the popular laxative tablets and lozenges sold 
extensively to the laity. The well-known mixtures of the " Castoria " 
type contain senna, pumpkin seed, chenopodium, anise, rochelle salt, 
sodium bicarbonate, honey, and sugar, flavored with oil of peppermint 
and methyl salicylate; and other popular syrups consist of extract of figs 
and senna with the addition of one or more of the drugs mentioned in 
the above combinations. 

Senna leaves are sometimes mixed with the pods. Senna siftings are 
imported in large quantities and formerly were always heavily adulterated 
with sand, some shipments containing from 25-40 per cent. 

Tutin x has made an exhaustive study of senna leaves and reviewed 
the researches of previous authors. He found that the only anthraquinone 
derivatives present were rhein and aloe-emodin. In addition to these 
well-defined constituents senna contains salicylic acid, a volatile oil pos- 
sessing a characteristic odor, kaempferol, Ci5H 6 02(OH)4, a flavone deriva- 
tive; kaempferin, a glucoside of kaempferol and glucose; a mixture of 
* Trans. Chem. Soc, 1913, 103, 2006. 



PURGATIVE DRUGS 371 

the glucosides of rhein and emodin, isorhamnetin melting 302° C, and 
glucosides of which this is a component; resinous matter from which 
myricil alcohol, palmitic and stearic acids, a phytosterol and phytostero- 
lin were isolated; and amorphous substances. 

Kaempferol (1-3-4 trihydroxyflavonol) is extracted from acid aqueous 
solutions by ether, and may be extracted from ether by dilute sodium 
carbonate. As obtained from an extract of the drug it is usually con- 
taminated with aloe-emodin, from which it may be separated by redis- 
solving in ether and shaking out with dilute sodium carbonate. By 
repeating this treatment the aloe-emodin finally will be left behind in 
the ether. Kaempferol can be crystallized by concentrating its solution 
in slightly diluted alcohol. It forms bright-yellow needles, melting 274°, 
colored yellow by alkalies and giving a strong blue fluorescent solution 
with concentrated sulphuric acid. It yields tetra-acetylkaempferol which 
when crystallized from ether, ethyl acetate, or alcohol forms colorless 
needles, melting 119-120°, and when resolidified melts at 183°. This 
is probably due to the presence of solvent of crystallization, because if 
the crystals are dried at 110° until no further loss in weight occurs they 
melt sharply at 183°. 

E. M. Bailey l considers that chrysophanic acid is a constituent of 
senna. 

When an extract of senna slightly acidified is shaken with ether, the 
ether solution will give the Borntrager reaction. If the ether solution is 
agitated with saturated solution of nickel acetate, the aqueous layer will 
develop a red color. On separating and adding potassium hydroxide 
solution a violet precipitate forms. Beal and Okey find that this reaction 
is characteristic of senna. Rhubarb and fiangula require the addition 
of alkali to produce a color change. Cascara gives an orange yellow 
which becomes dark red after adding alkali. Aloes gives yellow-brown. 

Henna leaves are obtained from Lawsonia inermis (Lythrariae) and 
are used in jaundice and for cutaneous disorders, including leprosy. They 
contain tannins and a yellow substance having powerful dyeing properties. 

The drug is sometimes confused with senna. 

CASCARA SAGRADA 

The bark and fruit of certain species of the Rhamnaceae contain anthra- 
quinone derivatives and Cascara sagrada or sacred bark from R. Purshiana 
has attained great renown as a laxative drug. 

The tree yielding the Cascara bark is indigenous on the western coast 
of the United States and its habitat extends north into British America. 

The fluid extracts, both plain and aromatized, are extensively used 
» Jour. Ind. and Eng. Chem., 1914, 6, 320. 



372 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

in medicine, and modified forms of the extract in which the bitter princi- 
ples have been removed or emasculated by magnesia, are of common 
occurrence. Cascara cordials contain Berberis aquifolium, and some of 
the compound extracts contain senna and aloin. Many firms offer a 
special preparation of Cascara under a fancy, or trade-marked name, in 
which they claim to have removed the bitter and griping principles of 
the drug and preserved all of its laxative features. Some of these prepa- 
rations are highly fortified with other laxative drugs and croton oil. 

Cascara is combined with malt extract, and with iron peptonate and 
manganese. It occurs in elixirs with senna, leptandra, butternut, and 
rochelle salt. 

In the form of pills and tablets Cascara will be found combined with 
aloin, strychnin (or Nux Vomica), and belladonna; rhubarb, Nux Vomica, 
and aloin; Podophyllum, colocynth, Hyoscyamus, butternut, Nux Vomica, 
gentian and Apocynum; belladonna, Capsicum, Nux Vomica, Euonymus, 
and Xanthoxylum; Podophyllum, strychnin, aloin, belladonna and ginger; 
Nux Vomica, belladonna, Podophyllum, and ipecac; Blaud's mass and 
Nux Vomica; sometimes with arsenous acid; quinin, reduced iron, strych- 
nin, and arsenous acid. 

It has been commonly asserted and generally believed, that Cascara 
bark must be stored for at least a year or two before it can be used, the 
claim being that fresh bark contains an enzyme which causes intense 
griping and which is destroyed on long standing. Jowett isolated an 
hydrolytic enzyme from the bark but found that it had no griping 
acid. 

When properly cured, the drug is just as available for producing 
medicines when it is a month old as when it has been stored for a year 
or two. 

The bark of Rhamnus californica sometimes enters into competition 
with the official drug. The tree occurs abundantly in the southern part 
of California, while Cascara is found sparingly in that locality. There 
are recognizable differences in the characteristics of the leaves of the two 
species, but the appearance of the barks is practically identical. Micro- 
scopically one will find structural differences sufficiently distinct to aid 
in the recognition of the drug; and when macerated with dilute alcohol, 
the powder of R. Purshiana appears yellow, that of R. californica purplish; 
with potassium hydroxide the former gives an orange-yellow color, the 
latter a blood red. 

The chemistry of the bark has been the subject of extended research, 
but much of the work is of little scientific importance. The bark con- 
tains resinous material, but this does not appear in large quantity in any 
of the extracts used in medicine because those extracts are obtained by 
water percolation. The only definite anthraquinone principle which 



PURGATIVE DRUGS 373 

Jowett isolated from the bark was emodin. He found no chrysophanic 
acid nor glucosides yielding emodin on hydrolysis. Iso-emodin has been 
reported. Syringic acid and rhamnol have been reported. 

An aqueous extract of the bark, after precipitation with lead acetate, 
contains substances which are thrown out by basic lead acetate and which 
subsequently, after removing the lead, yield emodin on hydrolysis. Dohme 
and Englehardt consider that basic lead acetate precipitates a glucoside, 
to which they give the name purshianin, but Jowett claims that he was 
unable to detect any glucosidic character in this body. In the course 
of his experiments with the extract the writer has isolated substances of 
a glucosidic nature, and while their chemical purity has not been estab- 
lished it appears probable that the bark contains anthraquinone deriva- 
tives of a more complex nature than emodin. 

THE BUCKTHORNS 

The bark of the stems and branches of the Alder buckthorn, R. fran- 
gula furnishes the official drug. The barks of R. cathartica, the common 
buckthorn, and of R. carniolica are probably sold for the official drug, 
as all of these shrubs grow in the same localities. 

The berries of R. frangula yield a juice formerly sold as Rhamni 
Succus. This juice, and that of the berries of R. cathartica, is still used 
as an hydragogue cathartic in the form of a syrup in combination with 
ginger and pimento. The combination appears to be useful in dropsy, 
rheumatism, and gout. 

The berries of these plants as well as those of R. infectoria and R. 
santiles are used for making yellow dyes. 

The frangula barks contain anthraquinone derivatives. Both of the 
common buckthorns contain a glucoside to which the name frangulin 
has been given, and which on hydrolysis yields rhamnose and emodin. 
The emodin of the buckthorn and Cascara sagrada are identical. Fran- 
gulin resembles the glucosidic substances of Cascara. It is precipitated 
by basic lead acetate, copper acetate, barium hydroxide, and ferric chlo- 
ride and gives a red solution with concentrated sulphuric acid. On hydrol- 
ysis it yields emodin and rhamnose. These drugs also contain flavanol 
derivatives soluble in concentrated sulphuric acid with a greenish-blue 
fluoresence. Rhein and chrysophanic acid have also been reported. 

The anthraquinone derivatives exist in greater quantity in R. fran- 
gula than in R. Purshiana, but their general character appears to be the 
same. It is probable that there is but little difference in the chemical 
constituents of these drugs, though considerable research is still needed to 
clear up the disputed points concerning their chemistry. 

Frangula bark gives a much stronger Borntrager reaction than Cascara 



374 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

sagrada, in fact the shade is as deep a crimson as that given by senna or 
rhubarb. 

When a dilute alcoholic extract of frangula is shaken with 4 parts of 
ether, and the latter agitated with saturated solution of nickel acetate 
no red color appears until potassium hydroxide is added to the aqueous 
layer when a deep red-violet precipitate is obtained, and the ether layer 
becomes colorless almost immediately. Cascara gives an orange-yellow 
before adding alkali; the latter then causes a dark red color. With rhu- 
barb the ether layer remains colored for a much longer period. 

GOA POWDER AND CHRYSAROBIN 

Goa powder is an irritant material deposited in cavities in the trunk 
of the Vouacapoua Araroba (Leguminosse) , a tree growing in Brazil and 
probably other South American countries. The powder is also known 
as Brazil powder, ringworm powder, crude chrysarobin, and Pao de Bahia. 
When fresh it is light yellow and bitter, becoming darker on exposure to 
the atmosphere. It consists of chrysarobin, gum, resinous matter, and 
woody fiber, and is often adulterated with powdered Andira wood. 

Goa powder is used as a remedy for skin diseases and for preparing 
chrysophanic acid. 

It is called "Arariba " powder, but this name should be used only 
to distinguish the barks of Sickingia viridiflora and S. rubra., which are 
of a different family. 

Chrysarobin is the name given to purified Goa powder obtained by 
extraction with chloroform. It is also called medicinal chrysophanic 
acid and is usually described as the neutral principle of the powder. This 
description is confusing as it is a mixture of several different substances, 
some well-defined and others not yet determined, and they are by no 
means all of neutral character. 

Chrysarobin is an orange-yellow microcrystalline powder darkening 
on exposure, soluble in chloroform and benzol with ease, less readily in 
ether and alcohol and partly and with some difficulty in water. It is 
soluble in potassium hydroxide to a deep brownish-red solution inclining 
to purple. It dissolves in concentrated sulphuric acid to a deep red 
solution. 

Tutin and Clewer 1 find that chrysarobin contains on the average 
about 5 per cent of chrysophanic acid, 2 per cent of emodin monomethyl 
ether, 46 per cent of the anthranol of chrysophanic acid, a small amount 
of the anthranol of emodin monomethyl ether, 18 per cent of dehydro- 
emodinanthranol-monomethyl ether, 4 per cent of ararobinol, C23H16O5, 
and 25 per cent of an inseparable mixture and amorphous material. 
»Proc. Chem. Soc, 1912, 28, 13, and 1913, 29, 285. 



PURGATIVE DRUGS 375 

The anthranol of chrysophanic acid (chrysophanol) , CisH^Oa, may 
be represented by the structural formula 

OH 

I 

OH. C .CHs 

>C 6 H 2 < >C 6 H 3 / 

oh/ x c / 

H 

It forms pale yellow leaves from chloroform, melting 204°. It is insoluble 
in aqueous alkalies. Its alcoholic solution gives a dark red-brown color 
with ferric chloride. When treated with chromic acid it is converted into 
chrysophanic acid. It gives an orange-red color with concentrated sul- 
phuric acid. 

Chrysarobin is chiefly employed as an external remedy in psoriasis, 
herpes tonsurans, and hemorrhoids. It is administered in the form of 
ointments, cerates, and collodion mixtures. For hemorrhoids it may be 
combined with iodoform and belladonna, and dispensed in vaseline oint- 
ments, or in glycerin or cocoa butter suppositories. 

Acetates of chrysarobin are sold under the names of Lenirobin and 
Eurobin. The former is described by its makers as a tetracetate, and is 
soluble in chloroform, acetone, and benzol, but insoluble in water. The 
latter, a triacetate, dissolves in the same solvents, and is dispensed in 
acetone. It may be found combined with saligallol (pyrogallol disalicy- 
late). They are used as substitutes for chrysarobin in skin diseases. 

DRUGS OF THE RUMEX GENUS 

The roots of Rumex crispus (Porygonacese), yellow or curled dock, 
and R. obtusifolius, bitter dock, are used medicinally. The former was 
official in the U. S. P. 1890. The roots of other species are probably 
sold indiscriminately with those of the two mentioned. 

Yellow dock is an alterative, tonic, and mild laxative. It is admin- 
istered in the form of a syrup combined with potassium iodide, magnesium 
sulphate, the bark of Celastrus scandens (False bittersweet), the bark 
and twigs of Parthenocissus quinquefolia (American ivy or Virginia 
creeper), and the root and plant of Scrophularia marilandica (Maryland 
figwort or carpenter's square). The solid extract is employed locally in 
skin diseases and the powdered root as a remedy for spongy gums. 

The chemistry of the dock roots has never been thoroughly investi- 
gated, but anthraquinone derivatives are present, and it is claimed that 
emodin and chrysophanic acid have been identified. 

The leaves of R. acetosella, the common sorrel or sour grass, are em- 
ployed in febrile, inflammatory, and scorbutic affections as a refrigerant 



376 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

and diuretic drug. They contain acid potassium oxalate and a little 
tartaric acid. 

The root of Polygonum cuspidatum syn., Pleuropterus zuccarinii (Poly- 
gnacese) the Japanese knotweed, is reported as containing free emodin 
and anthraquinone glucosides. This root has been confused with that 
of P. bistorta, which is apparently the true bistort and which contains 
much tannin. Bistort is used in acute and chronic intestinal catarrh, 
dysentery, amenorrhea, and in hair preparations designed to promote 
the growth of the hair. 

Methods for Identifying the Anthraquinone Drugs in Medicines. — 
It is obvious that there are several important drugs whose most prominent 
ingredients are anthraquinone derivatives and that in mixtures where 
they functionate as extracts, the absolute identification of one particular 
drug to the exclusion of all the others is not an easy matter. Further- 
more it has been demonstrated that there are several other drugs which 
contain those or similar derivatives, but whose general chemistry is not 
known, and which might easily be mistaken for the more common varieties 
when dispensed in the extract form. The separation and identification 
of the anthraquinone derivatives is possible only when one has a con- 
siderable quantity of material, much more than is usually offered as a 
sample for the analysis of a medicine. In mixtures of powdered drugs 
the microscopic character of the fibers and cellular structure will aid the 
analyst in arriving at absolute results, but in liquid or solid extracts where 
the structural characteristics are lost, he must depend upon the odor, 
color reactions, and presence of other principles normally occurring in 
the plant in order to determine the identity of the drug in hand. Often he 
can go safely only so far in his conclusions as to assert that anthraquinone 
derivatives are present. 

Preparations containing rhubarb will give a magenta coloration when 
subjected to the Borntrager reaction. Senna and frangula extracts also 
give intense crimson or magenta shades, while Cascara usually gives a 
lighter color more on the pink, and with aloes the color develops gradually. 

The essential oil of rhubarb has an unmistakable and characteristic 
odor and will furnish valuable evidence in establishing the identity of 
the drug. If an alcoholic extract is mixed with water and distilled with 
steam, the oil passes into the distillate and is readily recognized. This 
same odor is always apparent when running an alcohol determination on 
liquid preparations containing rhubarb. 

Gallic acid furnishes further evidence of the presence of rhubarb. 

The fractionation and identification of each and every anthraquinone 
derivative is impracticable, when working with medicines and about all 
that one can accomplish is to obtain conclusive tests for their identity. 

If aloes or aloin are simultaneously present with rhubarb, the odor, 



■«■■ 



PURGATIVE DRUGS 377 

presence of gallic acid and strong Borntrager reaction will distinguish the 
latter, while the odor of the aloes and identification of aloin as described 
under Aloes will distinguish the former. 

Reliable tests for senna and the Rhamnus drugs in presence of rhubarb 
have been worked out by Beal and Okey. Senna contains salicylic acid, 
which is of course easily separated by petroleum ether from an acid aqueous 
solution of the alcoholic extract of the mixture, but while this is indicative 
of the presence of senna it is by no means conclusive. Its absence, how- 
ever, indicates that there is no senna extract in the preparation, and is 
a point for the analyst to remember in case he is testifying and the cross- 
examiner seeks to confuse him regarding the identity of the components 
of the mixture in hand. Senna also contains kaempferol, which can be 
separated from the aloe-emodin of the drug as described and then subjected 
to proper tests for its identity. In ordinary cases under drug control 
laws it is a small matter analytically whether the drug present is absolutely 
identified or not. It is sufficient to assert that there was found a drug 
or drugs containing anthraquinone derivatives, and as these are of limited 
number and of similar physiological action it matters little analytically 
whether the formula is composed of one or all of them. 

The quantitative estimation of the anthraquinone derivatives in these 
drugs or in mixed medicinal preparations containing no phenolphthalein 
may be accomplished according to the second method of assay given 
under Rhubarb, on page 62. 

Bailey 1 differentiates between the anthraquinone derivatives by pre- 
paring an alcoholic extract of the sample under examination, evaporating 
the solvent, diluting with 25 mils of water, precipitating with lead acetate 
and filtering. The lead precipitate is transferred to a beaker and digested 
for one hour on a water-bath with 10 per cent sulphuric acid. The solu- 
tion is filtered and while still hot, is extracted with benzol. 

The benzol solution is washed first with 25-mil portions of 5 per cent 
ammonium carbonate until the washings are colorless or but faintly colored, 
then with similar portions of 5 per cent sodium carbonate until the wash- 
ings become pink, and finally with 5 per cent sodium hydroxide. He 
found that ammonium carbonate removed arithraquinone derivatives 
which he did not identify, sodium carbonate removed emodin and sodium 
hydroxide removed chrysophanic acid. The three aqueous solutions are 
^hen separately acidified, shaken out with ether, and the ether residues 
examined directly or after recrystallization from alcohol. 

A few drops of the ether residue is treated with 4 to 5 drops of con- 
centrated sulphuric acid, then 1 to 2 drops of concentrated nitric acid, 
and, finally about 1 mil of water. 

In the case of chyrsarobin a little color is removed by the first two 
1 Amer, Jour. Pharm., 1915, 87, 145. 



378 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

reagents, but the bulk of the color goes into sodium hydroxide with one 
washing. The ether residue gives orange red with sulphuric acid, becom- 
ing yellow with nitric acid and giving a yellow solution and a flocculent 
precipitate with water. 

With Rhamnus frangula most of the color is removed by the sodium 
carbonate and the ether residue gives an intense pink with sulphuric acid, 
becoming yellow with nitric acid and pink with water. 

With rhubarb, both the sodium carbonate and hydroxide fractions 
are colored, the ether residue of the former reacted similarly to the emodin 
body derived from R. frangula, and the color test with the ether residue 
from the latter were the same as for chrysophanic acid from chrysarobin. 

With senna, a considerable quantity of color goes into the ammonium 
carbonate fraction to an orange-colored solution, and on separation the 
residue obtained is not homogeneous, being partly insoluble in ether. 
The ether-soluble portion gives a purple or violet color with sulphuric 
acid, becoming yellow with nitric acid and remaining yellow on adding 
water. The ether-insoluble portion gives a purple-red solution with sodium 
hydroxide which is not discharged by zinc dust, and on dilution with 
hydrogen peroxide the color fades and a light-colored precipitate settles. 
Sodium carbonate and hydroxide remove coloring matter from the benzol 
and the residues finally obtained react for emodin and chrysophanic acid 
respectively. 

With aloes, ammonium carbonate removes considerable color, the 
washings being orange colored. The ether residue gives a purple color 
with sulphuric acid, turning yellow with nitric acid and unchanged with 
water, corresponding to the substance obtained from senna. Sodium car- 
bonate removes but a small quantity of material, and an ether residue 
gives a red to brownish with sulphuric acid, turning yellow with nitric 
acid and unchanged by water. The greater part of the color is removed 
by sodium hydroxide and the ether residue reacts similarly to the chryso- 
phanic acid obtained from the other sources. 

Phenolphthalein interferes with the Borntrager reaction and may be 
removed as the iodin compound by a method evolved by Warren. 1 

The preparation in the form of a thick syrup is diluted with water, 
faintly acidified, and filtered. The filtrate is evaporated to a thick syrup 
and, while still warm, is extracted with acetone slightly acidified with 
hydrochloric acid. The acetone extract is evaporated to dryness on a 
water-bath, the residue twice moistened with alcohol, and the alcohol 
evaporated in order to remove the last traces of acetone. 

The residue is dissolved in dilute sodium hydroxide, iodin added, 
followed by hydrochloride acid, which precipitates tetraiodophenolphtha- 
lein. After cooling for an hour below 15° C, the iodin compound is 
1 Amer. Jour. Pharm., 1914, 86, 444 



PURGATIVE DRUGS 379 

filtered off, the excess of iodin removed by sodium sulphite, and the 
solution extracted with benzol to remove the anthraquinone derivatives. 

One of the most important contributions to the chemistry of these 
drugs from an analytical standpoint was made by Beal and Okey and to 
which reference has been made several times in this chapter. 

A small amount of a dilute alcoholic solution of the drug preparation 
is shaken with 4 volumes of benzol, separated and the benzol solution 
shaken with 30 per cent sodium hydroxide. A light red to deep violet 
color indicates anthraquinone drugs. If the color is due to phenolphtha- 
lein it will disappear quickly, that due to the other drugs will remain 
unchanged. 

If the above test is positive, a portion of the benzol is evaporated, 
moistened with nitric acid and again evaporated. The residue will be 
red or orange-red, and when treated with potassium cyanide or 30 per 
cent alkali will take a red or purplish-red with anthraquinone drugs. 
Phenolphthalein gives a brownish color. If the latter is present it should 
be removed by the method of Warren. 

The dilute alcoholic solution is then divided into three portions, A, 
B, C. 

Portion A is shaken with 4 parts of benzol and subsequently with 
amyl alcohol. A portion of the benzol solution is shaken with concen- 
trated ammonia, a deep red-violet color with a precipitate of the same 
color settling between the liquids indicates rhubarb. This is confirmed 
by the lead subacetate test, yellow-orange precipitate, turning red with 
alkalies. (If a concentrated alcoholic solution of the drug is precipitated 
with water, the resinous matter filtered off, washed, dried, and treated 
in a porcelain dish with alcohol, sodium peroxide, and water, a red color 
appears in the alcohol, turning orange-red on the addition of water. The 
other drugs impart no color to the alcohol, but yield various shades of 
orange with water.) 

The amyl alcohol shake-out is divided to 4 portions. One portion is 
shaken with strong ammonia, and the development of a deep-red color 
and a dark green fluorescence indicates aloes and fresh Cascara. If positive, 
another portion is shaken with a saturated solution of mercurous nitrate 
containing a slight excess of nitric acid; in the presence of aloes a deep-red 
color develops in the aqueous layer, reaching its height in six to eight min- 
utes, fading to reddish-brown. If a small quantity is present the color is pink. 
Another portion is evaporated, taken up with dilute alcohol and treated 
with copper sulphate and hydrogen peroxide and boiled, a red color will 
appear in presence of aloes. Another portion should be evaporated and 
tested with borax solution to obtain the characteristic green fluorescent 
solution. If Cascara is indicated, a portion is evaporated, the film mois- 
tened with nitric acid, evaporated to dryness, treated with stannous chlo- 



380 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

ride containing a little free hydrochloric acid, decanted, washed with jet 
of water, and treated with alcohol; deep-red color indicates cascara; aloes 
gives yellow brown. 

Portion B above is then shaken with 4 parts of ether and divided into 
several fractions. One portion is shaken with saturated solution of nickel 
acetate, and if the aqueous layer is red, senna is indicated. If the solu- 
tion remains green and subsequently gives a green precipitate with potas- 
sium hydroxide, but preliminary tests have shown a permanent color with 
alkali, rumex is indicated. (The authors apparently used Rumex eckloni- 
anus in these researches.) The reagent and the ether must be kept mixed 
when the alkali is added. When shaken with alkali, a violet precipitate 
will appear if senna is present; a red- violet precipitate with rhubarb or 
frangula; and a dark orange-red color with Cascara. Rhubarb and fran- 
gula give orange solutions before adding alkali. The ether layer after 
adding alkali, will become colorless almost immediately, except in pres- 
ence of rhubarb, when it persists. 

If conclusive evidence is not obtained, a portion of the ether solution 
is evaporated, nitrated, and treated with stannous chloride as above 
described. Senna gives a green residue; aloes brown; Cascara red; Rumex, 
rhubarb, and frangula violet-red; phenolphthalein lemon-yellow. The 
excess of stannous chloride should be removed with water, the residue 
treated with U. S. P. solution chlorinated soda, and if a red color appears 
senna is present. 

PODOPHYLLUM AND PODOPHYLLOTOXIN 

The well-known mandrake or May apple, Podophyllum peltaltum 
(Berberidacese) , is a common plant of the rich woodlands east of the 
Mississippi. It grows in dense patches and is one of the most conspicuous 
plants in the early spring throughout its range. 

The rhizome contains an irritant resin, sometimes called podophyllin, 
which is extensively used in remedies for liver and bowel complaints. 

Podophyllum resin is one of the constituents of a great many formulas 
containing cathartic drugs, and will be found in various combinations 
with aloin, strychnin, or Nux Vomica, belladonna or Hyoscyamus, Capsi- 
cum, ipecac, Colocynth, jalap, scammony, gamboge, Cascara sagrada, 
juglans, gentian, leptandra, oil of peppermint, mercury mass, croton oil, 
soap, Veratrum, and Apocynum. It enters into the compound cathartic 
pills of the U. S. P. with colocynth comp., Hyoscyamus, jalap, leptandra, 
and oil of peppermint; it is combined with santonin, with calomel and 
sodium bicarbonate; with Hydrastis canadensis; with Euonymus; with 
Cimicifuga; with quinin or cinchonidin, arsenous acid, Gelsemium, pepper, 
and ferrous sulphate; and often it is dispensed by itself. 



PURGATIVE DRUGS 381' 

It is combined with castor oil in elastic capsules. Fluid extract man- 
drake compound contains extract of Podophyllum, senna, leptandra, and 
jalap; and it is present in fluid extract dandelion compound with Tarax- 
acum and Conium, 

One of its purified active principles, podophyllotoxin, is used quite 
extensively as a remedial agent. 

The valuable constituent of the rootstock is a resin amounting to 
3.5-5 per cent, containing podophyllotoxin and picropodophyllin, an 
isomeric substance. The former is slightly soluble in water, the latter 
insoluble in water. The resin is intensely irritant to the mucous mem- 
brane and, unless carefully handled, produces conjunctivitis. 

The rhizome of P. emodi, a plant growing on the lower slopes of the 
Himalayas, is larger and yields 11-12 per cent resin, but is only half as 
rich in podophyllotoxin. 

The chief constituent of the resin is podophvUotoxin, a neutral sub- 
stance possessing the formula 

C 2 oHi 5 6 (OCH3)3+2H 2 0, or C15H14O6+2H2O, 

crystallizing in prisms, melting 94° C. (117° reported), strongly lsevo- 
rotatory. When heated with alkalies it is converted by hydration into 
the salt of an unstable gelatinous acid, podophyllic acid, C15H16O7. This 
acid loses water and furnishes the crystalline picropodophyllin isomeric 
with podophyllotoxin, melting 227° and optically inactive. It passes 
again into podophyllic acid when warmed with aqueous alkalies. Podo- 
phyllotoxin and picropodophyllin furnish identical decomposition products; 
when oxidized with nitric acid, oxalic acid is the principal product; when 
fused with alkalies, orcinol and acetic acid are produced. Both substances 
contain three methyl groups and no hydroxyl. 

The yellow coloring matter of the drug is identical with quercetin, 
the yellow coloring matter of quercitron bark. An amorphous resin called 
podophylloresin is present in the drug. • 

Podophyllotoxin is prepared commercially by digesting the resin with 
chloroform, filtering, concentrating to a thick syrup, and treating with 
alcohol-free ether as long as a precipitate is obtained. The clear liquid 
is then decanted and concentrated and the syrupy residue poured into 
petroleum ether, when the commercial podophyllotoxin is precipitated. 

An extract of mandrake when subject to Borntrager's test gives a 
bright-yellow color with ammonia before boiling with acid and an amber 
color afterwards. This coloration is probably produced by the yellow 
coloring matter naturally present in the drug. 

Determination of Resin in the Drug or Extract. — W. M. Jenkins 1 
has based a method on the ready solubility of the resin in a mixture of 
1 J. Ind. and Eng. Chem., 6, 1914, 671. 



382 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

alcohol-chloroform 1-2. Five mils of the fluid extract are shaken with 
5 mils of alcohol, 10 mils of chloroform, and 10 mils of acidulated water 
(0.6 per cent hydrochloric acid). The lower layer is drawn off and the 
aqueous solution extracted twice with 15-mil portions of the alcohol- 
chloroform mixture. The united extracts are washed with 10 mils of 
acidulated water, and the aqueous layer again shaken twice with 15 mils 
of the solvent mixture. The combined extracts are evaporated and the 
residue at 100° C. weighed. 

The drug is first extracted with alcohol by hot maceration and 10 
mils of the extract, equivalent to 2 grams of the drug, are treated as 
described above except that the addition of 5 mils alcohol is omitted. 

The determination of the podophyllo toxin is often important, but at 
present the methods in use leave much to be desired. There are two types 
of procedure, that of the Dutch Pharmacopoeia and the lime method. 
The former gives about one and one-half times as much podophyllotoxin 
and is based on the difference in solubility in petroleum ether, after a 
chloroformic extraction, of the resin and the neutral crystalline principle. 

The lime method really amounts to a conversion of the podophyllo- 
toxin to the isomeric picropodophyllin and weighing it as such. The 
procedure recommended by Gordin and Merrell * is as follows: 

Five grams of the resin and 10 grams of freshly prepared calcium 
hydroxide are placed in a strong, well-corked bottle of about 200 mils 
capacity and the whole weighed. The bottle is then uncorked, heated 
for a few minutes on the water-bath at 60-65°, 15 mils of alcohol added, 
the whole well shaken and the closed bottle kept on the water-bath for 
eight hours, shaking the first few minutes to prevent the formation of 
a hard lump and then every fifteen minutes. The bottle is then cooled, 
about 7 mils of chloroform added, then enough of a mixture of 2 parts 
alcohol-1 chloroform (by vol.) to make the whole liquid weigh 130 grams. 
After shaking for a few minutes the bottle is allowed to stand for twenty- 
four to forty-eight hours, 65 grams of the clear liquid drawn off into a 
tared dish, the solvent distilled off and the residue weighed. 

JALAP AND SCAMMONY 

Several species of plants belonging to the Convolvulacese contain 
purgative resins, which have an extensive medicinal use. The two most 
important are Exogonium purga (Ipomcea purga), which furnishes the 
dried tuberous root known as jalap, and Convolvulus scammonia, which 
furnishes the , gum resin known as scammony. In addition, Ipomcea 
purpurea contains resinous constituents which are apparently similar, 
and is sometimes substituted for jalap resin, and the root of I. orizabensis 
^roc. Amer. Pharm. Ass., 1902; J. Soc. Chem. Ind., 1902, 1362. 



PURGATIVE DRUGS 383 

(Mexican Scammony) has partially displaced true Scammony. Power 
and Rogerson 1 have reported an investigation of the tuberous root of I. 
horsfallise, but the resin therefrom was in small quantity and apparently 
devoid of physiological properties. 

JALAP 

The only constituent of the tuber possessing interest to the drug 
chemist is the resin. This is obtained by an alcoholic extraction of the 
ground drug, the residue left on evaporation the solvent being washed 
and dried. About 10 per cent of this resin is soluble in ether, and about 
25 per cent is subsequently dissolved in chloroform. The U. S. P. stand- 
ard of not over 30 per cent chloroform-soluble matter in resin of jalap 
is indefinite, as \ariable amounts are removable from the resin according 
to the method employed. When the resin is stiired with the solvent in 
the cold, it is not completely extracted after nineteen or twenty additions 
of chloroform, and the large number of fractions required renders the 
procedure impracticable. The quantity dissolved in the cold by this 
method is much less than that taken up by hot chloroform when the 
sample is subjected to a Soxhlet oi Knorr extraction. In fact some samples 
of jalap resin yield over 90 per cent to the solvent, when subjected to the 
Soxhlet method. 

The adulterants of jalap resin include colophony, guaiac, myrrh, 
Tolu balsam, and the resin from aloes, jalap stalks, and Fungus Laricis 
(Dieterich). 

Jalap resin is used in several well-known cathartic mixtures dispensed 
in the pill or tablet form. In the liquid form, extract of jalap is combined 
with the extracts of Podophyllum, senna, leptandra in fluid extract man- 
drake compound; and with senna and coriander in fluid extract senna 
compound. The types of pill mixtures contain in addition to jalap resin, 
colocynth comp., colocynth, aloes, cardamom, scammony, soap, Podo- 
phyllum, Capsicum, and Hyoscyamus; leptandra, aloin, Podophyllum, 
gamboge, Capsicum, Hyoscyamus, and peppermint oil; similar formulas 
with Nux Vomica or gentian or calomel, or rhubarb; liver pills with aloes, 
gamboge, leptandra, Capsicum, Veratrum viride, croton oil, calomel, or 
Podophyllum; aloes, mercury mass, and tartar emetic; and the U. S. P. 
vegetable cathartic consisting of colocynth comp., Hyoscyamus, jalap, 
leptandra, Podophyllum, and peppermint oil. 

The chief portion of jalap resin is insoluble in ether and is commonly 

designated as " convolvulin," and the ether soluble portion as " jalapin," 

though originally the latter term was applied to the chief portion of the 

resin, which was insoluble in ether. These terms have little significance 

1 Am. J. Pharm., 1910, 82, 355, 



384 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

at the present time, however, as Power and Rogerson have published the 
results of a carefully conducted research, the essentials of which may be 
summarized as follows: 

The total crude resin, when purified by means of animal charcoal, 
had a specific optical rotation of —37.0°. On extracting the crude resin 
successively with (I) light petroleum (b.p. 40-60°), (II) ether, (III) 
chloroform, (IV) ethyl acetate, and (V) alcohol, a number of products 
were obtained, the examination of which has shown the resin to be of 
much more complex composition than has previously been assumed. 

I. Petroleum Extract of the Resin. — This represented 1.9 per cent of 
the total resin. It contained palmitic and stearic acids in a free state, 
and, after hydrolysis, yielded formic, butyric, and higher volatile acids, 
palmitic acid, and a mixture of unsaturated acids, which appeared to 
consist chiefly of linolic acid. From the unsaponifiable portion of the 
extract there were obtained a phytosterol, C27H46O (m.p. 134-135°, 
(a) D — 32.4°), cetyl alcohol, C16H34O, and a small amount of a substance 
melting at 56-57°, which agrees in composition with the formula C18H36O. 
This substance, which appears to be a new compound, yields color reac- 
tions similar to those of the phytosterols. 

II. Ether Extract of the Resin. — This represented 9.7 per cent of the 
total resin. From it there was isolated a small amount of a new, dihydric 
alcohol, which possesses the formula C2iH3202(OH)2, and is designated 
ipurganol. Ipurganol crystallizes in colorless needles, melting at 222- 
225°, and has, in pyridin solution (a) D — 44.9°. It yields color reactions 
similar to those given by the phytosterols. Diacetylipurganol, 
C2iH320 4 (CH3-CO) 2 , forms colorless leaflets, melting at 166-167°, and 
has, in pyridine solution, (a) D — 36.0°. The ether extract, after treat- 
ment with alkalies and dilute sulphuric acid, yielded, furthermore, a little 
phytosterol and acetyl alcohol, small amounts of volatile acids, and a 
quantity of amorphous products. 

III. Chloroform Extract of the Resin. — This represented 24.1 per 
cent of the total resin. From it there was isolated a very small amount 
of /S-methylsesculetin, C 9 H 5 (CIl3)04. After treatment with alkalis and 
dilute sulphuric acid this extract yielded, furthermore, formic, butyric, 
and d-methylethylacetic acids, together with convolvulinolic acid, 
C15H30O3, and apparently a higher homologue of the latter. Glucose was 
also produced by this treatment, thus indicating that a portion of the 
extract was of a glucosidic nature. 

IV. Ethyl Acetate Extract of the Resin. — This represented 22 per cent 
of the total resin. On treatment with dilute alcoholic sulphuric acid, 
it yielded formic, butyric, and d-methyletlrylacetic acids, together with 
convolvulinolic acid, and apparently a higher homologue of the latter, 
having the composition C17H34O3. It also yielded, besides indefinite 



PURGATIVE DRUGS 385 

amorphous products, a considerable quantity of a sugar, which was evi- 
dence that at least a portion of the extract was of a glucosidic nature. 

V. Alcoholic Extract of the Resin. — This represented 38.8 per cent 
of the total resin. After treatment with animal charcoal it was obtained 
in the form of a nearly white powder, which melted at 150-160°, and had 
(o)d— 37.1°. When fused with potassium hydroxide it yielded formic, 
acetic, butyric, valeric, and higher volatile acids, together with azelaic 
and sebacic acids. When subjected to alkaline hydrolysis with baryta 
it yielded, besides small amounts of formic and butyric acids, d-methyl- 
ethylacetic acid, C 5 Hi O 2 (b.p. 174-176°; («)/>+ 17.55°), together with 
a quantity of an amorphous product, readily soluble in water, which may 
be designated as the hydrolyzed resin. This has now been shown to be 
of very complex composition, for by successive extraction with (a) ether, 
(b) chloroform, (c) ethyl acetate, and (d) alcohol it is capable of being 
resolved into a number of products. 

(a) Ether Extract of the Hydrolyzed Resin. — This extract, on heating 
with dilute sulphuric acid, yielded formic, butyric, and other acids, together 
with sugar. 

(b) Chloroform Extract of the Hydrolyzed Resin. — This extract, like 
the preceding one, yielded small amounts of formic, butyric, and other 
acids, together with sugar. 

(c) Ethyl Acetate Extract of the Hydrolyzed Resin. — This extract, on 
heating with dilute sulphuric acid, yielded formic, butyric, d-methylethyl- 
acetic, and other acids, together with sugar. 

(d) Alcohol Extract of the Hydrolyzed Resin. — This extract could be 
obtained in the form of a nearly colorless powder, which melted at 110— 
115°, and had {a) D — 33.53°. When heated with dilute sulphuric acid 
it yielded, in addition to sugar, small amounts of formic, butyric, and 
valeric acids, together with convolvulinolic and ipurolic acids. The last 
mentioned acid possesses the formula Ci3H 2 5(OH)2-C02H, and was first 
obtained by the authors from the stems of Ipomcea purpurea, Roth. 1 

By the oxidation of this extract with nitric acid, azelaic and sebacic 
acids were obtained. 

Each of the above-described extracts of the hydrolyzed resin appeared 
to be only partly glucosidic, and to contain a readily soluble organic acid 
which was unaffected by the treatment with dilute sulphuric acid. 

Scammony 

The gum-resin, obtained by incision of the horny root, is commonly 
designated as scammony or virgin scammony. Its value as a purgative 
agent depends on its resinous constituent, which is now generally obtained 
1 Am. J. Pharm., 80, 273 (1908). 



386 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

by extracting the dried root with a suitable solvent and washing the 
resinous mass with water until it comes away clear. The resin obtained 
by this means is almost completely soluble in ether, and the ether soluble 
portion has been termed " scammonin," being synonymous with the 
" jalapin " or ether soluble portion of jalap resin. 

Scammony resin is not used as largely as jalap, but it will be found 
in cathartic pills and tablets combined usually with colocynth, and con- 
taining in addition Podophyllum, soap, aloes, cardamom, and potassium 
sulphate. It is one of the ingredients of powdered extract colocynth 
compound, and as this product enters into the composition of a large 
variety of formulas the presence of small quantities of scammony may 
be expected whenever colocynth is discovered. 

Power and Rogerson 1 examined the root of Convolvulus scammonia, 
and found it to contain about 10 per cent of resins. They also identified 
sucrose, scopoletm, melting 203-204°, giving a beautiful blue fluorescence 
with alkalies, and 3-4 dihydroxycumaric acid. The resin which they 
obtained by alcoholic extraction was soluble to the extent of 90-95 per 
cent in ether, and thus differed markedly from the resin of jalap. Its 
rotation in absolute alcohol was (a) D — 19.87°. It has a peculiar and 
characteristic odor which is brought out on warming or by rubbing in 
a mortar. The resin yielded a phytosterol, melting 135-136°, soluble 
in petroleum ether, compounds of palmitic and stearic acid, ipuranol, 
C33H56O6, and on hydrolyzing with barium hydroxide, d-a-methyl butyric, 
tiglic, formic, and valeric acids, meth yl jalapinolate f| melting 47-49°, 
and jalapinolic acid, melting 67-68°, a mixture of sugars, and indefinite 
bodies. Ipuranol appears to be a phytosterol glucoside which on hydrol- 
ysis with aqueous hydrochloric acid is resolved into a phytosterol, 
C27H46O12, and glucose. 

The same authors examined virgin scammony and found it to be 
soluble to the extent of 80-85 per cent in ether, and to contain in addition 
to the substance mentioned above, small amounts of hentriacontane 
C31H64, and cetyl alcohol. 

The saponification number of the resin runs from 230-240 (Taylor) 
or 263 (Cowie). 

Scammony resin is adulterated with rosin, chalk, starch, resinous 
material and extractives from other drugs and Dieterich reports a case 
of adulteration with lead sulphide. 

Mexican Scammony 

The root of I. orizabensis is known under various names, such as Light, 
Fusiform, or Woody Jalap, or Orizaba Root (see Holmes, Pharm. J., 
1904, 72, 326). 

1 Chem. Soc. Trans., 101, 1912, 398. 



PURGATIVE DRUGS 387 

It contains about 15 per cent of crude resin, of which from 70-75 per 
cent is soluble in ether. 

Power and Rogersons' 1 investigation of this drug may be summarized 
as follows: 

From the portion of the extract which was soluble in water, the follow- 
ing compounds were isolated: (1) scopoletin, CioHgC^ (m.p. 203-204°), 
a small proportion of which appeared to be present in the form of a gluco- 
side; (2) 3:4 dihydroxyciimajiiic acid, CgHsO^ (m.p. 223-225°), from 
which the methyl ester (m.p. 158-160°) was prepared. The aqueous 
liquid contained, furthermore, a quantity of sugar, which yielded d-phenyl- 
glucosazone (m.p. 205-206°). 

The portion of the alcoholic extract which was insoluble in water 
consisted of a resin which possessed the above-mentioned characteristics. 
The resin was first successively extracted with various solvents, and the 
resulting extracts were then further examined. 

I. Petroleum Extract of the Resin. — From this extract the following 
substances were obtained: (1) hentriacontane, C31FL34; (2) a phytosterol, 
C27B46O; (3) cetyl alcohol, C16H34O; (4) a mixture of fatty acids, con- 
sisting of palmitic, stearic, oleic, and linolenic acids. 

II. Ethereal Extract of the Resin. — The optical rotatory power of 
this extract was (a) D — 20.5°. After hydrolysis with barium hydroxide 
it yielded: (1) ipuranol, C23H3s02(OH)2; (2) (/-a-methylbutyric acid; 
(3) tiglic acid; and a product which on acid hydrolysis, gave (4) jalap- 
inolic acid, CioHsoCOH) -C0 2 H (m.p. 67-68°); (a)z>+0.79°), together with 
a little methyl jalapinolate, and (5) a mixture of sugars, consisting of 
dextrose and a methylpentose. The latter yielded an osazone melting 
at 180-182° and a tetra-acetyl derivative, C 6 H s 5 (CO-CH3)4, which 
apparently is a new compound. Tins derivative crystallizes in handsome, 
prismatic needles, melting at 142-143°, and has (a).o+21.64°. The ethyl 
acetate extract of the product resulting from the alkaline hydrolysis of 
the ethereal extract of the resin gave on oxidation with nitric acid a mix- 
ture of acids, consisting apparently of optically active valeric and hexoic 
acids, together with sebacic and n-nonanedicarboxylic acids. 

III. Chloroform Extract of the Resin. — This was relatively small in 
amount, and consisted of a dark resinous product. 

IV. Ethyl Acetate Extract of the Resin. — The optical rotatory power 
of this extract was (a) D — 28.01°. After hydrolysis with barium hydroxide 
it yielded products from which the same substances were obtained as 
from the ethereal extract of the resin, with the exception of the small 
amount of ipuranol. 

V. Alcohol Extract of the Resin. — This was a black, amorphous prod- 
uct of a glucosidic nature, but which yielded nothing definite on hydrolysis. 

iChem. Soc.'Trans., 1912, 101, 1. 



388 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

It may also be noted that the portion of the resin which is soluble 
in ether is not identical with the ether-soluble portion of jalap resin. 

It has a saponification value of about 186-188 (Taylor) 295-327 
(Cowie). 

While there are some minor differences between the composition of 
the resin of this root and that of C. scammonia thus far ascertained, it 
is apparent that the resins could readily be substituted for each other with 
little chance of certain detection and as will probably be demonstrated, 
they are equally valuable for medicinal purposes. 

IPOMOEA TTJRPETHUM 

The root of I. turpethum, an East Indian species, yields a gum resin 
similar to jalap resin in its properties. This resin is called Turpeth and 
is used medicinally. Reports of its composition have appeared, but they 
require confirmation and further research. It is soluble in alcohol but 
insoluble in ether. 

Dieterich reports the following constants: acid value 20.55-24.45; 
ester value 137.27-141.01; saponification value hot 160.49-163.94. 

Examination of Resins. — In order to test these resins for adulterants 
a few simple determinations should be made and the results compared 
with those obtained with authentic specimens. 

Cowie recommends the following tests for Jalap resin, the same pro- 
cedure being applicable to the others: 1. Moisture. 2. Ash. 3. Solu- 
bility in ether, obtained by rubbing the sample in a mortar with ether, 
filtering and evaporating the solvent in a tared dish. 4. Acid value, 
obtained by dissolving in alcohol and titrating. 5. Saponification value. 
One hour's boiling with N/2 alcoholic potash and titration with N/2 
hydrochloric acid. 6. Absence of colopheny, .25 gram in 5 mils acetic 
anhydride should give no purple color with 2 drops of strong sulphuric 
acid. 7. Absence of guaiacum, no greenish-blue color with ferric chloride. 
8. Treatment with water results in no water soluble substance nor any 
starch reaction. 

Cowie 's results obtained by applying these tests to authentic resins 
yielded the following data: 



Brown Jalap resin 

Cowie White Jalap resin . . 
White Scammony resin . . . 
Brown Scammony resin . . . 
Mexican Scammonv resin. 



Moisture, 

Per Cent. 



O-o. b 

3-3.1 
2.52-5.3 
4.5-5.1 
2-3 . 05 



Ash, 

Per cent. 



0.3 

0.02 

0.02 

.15 

16-. 20 



Ether 
Soluble, 
Per cent. 



10 

0.3 

100.0 

95 

68.6-72 



Acid 
\ alue. 



Sapon. 
Value. 



11 

2.8 

2.8 

25.2 

8.4 



2-14 



-28 



333-338 
417 
241 
263 

295-327 



PURGATIVE DRUGS 



389 



Taylor's 1 results below with true and Mexican Scammony resins do 
not agree with Cowie's, but the differences may be due to the methods 
of analysis. Taylor dilutes with water before titrating with acid to 
determine the saponification value. 



Moisture, 
Per Cent. 



Ash, 
Per Cent. 



Ether 
Soluble, 
Per Cent. 



Acid 
Value. 



Sapon. 
Value. 



True Scammony 
Mexican Scammony. 



1.65-1.86 
1.77-2.03 



05-. 20 
09-. 22 



99-99.7 
96.5-99.6 



15.6-21.3 
15.5-21.5 



238-240 
186.6-187 



Evans Sons, Lescher, and Webb consider that the ester value of the 
resin is the most important factor in differentiating the source. They 
report the following data: 



Acid Value. 



Sapon. Value. 



Ester Value. 



Iodine Number. 



Jalap 

Virgin Scammony. . . 
Mexican Scammony 



8.4-26 
7-12 
11.2-24.1 



144.8-185 
240-250 
172.5-202.7 



121.8-162 

233-242.7 
161.3-178.6 



9-24.2 
3.6-9.6 
8.3-15.3 



Boudier 2 states that pure scammony resin should not give an acid 
number above 21 nor a saponification value below 235. 

Weigel 3 gives Asiatic scammony resin an acid number from 14-28, a 
saponification value 179-228; and Mexican Scammony 14.6 and 180-185. 
Jalap resin, acid number 12.6-16.8, saponification value 162-185. He 
considers that the acid value has greater significance than the saponifica- 
tion value. 

It has been suggested that the specific rotatory power might aid in 
detecting adulterants in, and discriminating between these resins. The 
resin obtained by extracting scammony root with a solvent has a rotation 
varying from —18° 30' to —23° 30' and the upper limit for the resin from 
the natural scammony is —25°. Mexican scammony rotates from —23° 
30' to -25°. The rotation of jalap resin is -36° to -37°, that of I. 
turpethum is high and that of I. purpurea —50 to —95°. The addition 
of colophony, sandarac, or mastic would lower the rotatory power, as their 
direction is dextro. 

It is apparent from the preceding review of the resins of the Convol- 
vulacese that their absolute identity in complex mixtures with other drugs 
is a matter of considerable difficulty. They are usually accompanied by 
other resinous drugs, and, while as a rule a mixture containing jalap will 

1 Am. J. Pharm., 1909, 81, 105. 
1 J. Pharm. Chem., 5, 97 and 154. 
3 Pharm. Zentralhalle, 51, 721. 



390 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

not contain scammony, jalap preparations often include extract of colo- 
cynth compound which has a little scammony in its make up. 

In the general scheme of analysis the resins will be extracted from the 
sample by alcohol, and, on driving off the solvent and treating the residue 
with water, they will be left behind in the dish. If this resinous mass is 
completely soluble in ether, the absence of jalap is established, but not 
necessarily the absence of the commercial " jalapin." If a residue is left 
undissolved, it may be freed from ether by warming and a portion treated 
with concentrated sulphuric acid, which will produce a brown to blood- 
red with a noticeable jalap-like odor if the drug is present. The balance 
of the residue is treated with chloroform and filtered, the chloroform solu- 
tion shaken with sodium carbonate, which will show a marked blue fluores- 
cence due to j3-methylaesculetin. This reaction can be rendered more 
certain by drawing off the alkaline solution, acidulating, filtering, and 
shaking with ether, discarding the acid liquid, and finally shaking the 
ethereal solution with ammonia, when a fine blue fluorescence will be 
obtained. A similar reaction will be obtained if Gelsemium is present 
in a mixture, but this drug can be readily distinguished from jalap by 
its characteristic alkaloids. 

That portion of the resinous matter which is soluble in ether will con- 
tain scammony and on evaporating the solvent and warming the residue 
with sodium carbonate solution it will not entirely dissolve, and the 
insoluble portion after washing and drying will swell up to a yellow mass 
with nitric acid. 

There are no methods for the accurate quantitative determination of 
resins or for separating one from the other. It is easy to determine the 
total amount of resinous matter in a drug mixture, but as nearly every 
vegetable drug contains some material of this nature, and as jalap and 
scammony are usually combined with other drugs, any estimate of resin 
will under such conditions be of little value. 



CHAPTER XII 

MISCELLANEOUS ACTING DRUGS 

SANTONIN AND PRINCIPLES OF THE ARTEMISIAS AND CERTAIN ALLIED 

DRUGS 

The genus Artemisia of the tribe Anthemidea? (Composita?) embiaces 
over two hundred species, some of which are of value as medicinal agents. 
The flowering tops of A. cina, A. maritima, A. gallica, and perhaps others 
contain santonin, a substance of peculiar lac tone-like composition which 
has a specific action on ascarides and lumbricoids. On this account san- 
tonin has become an important remedy for the expulsion of worms, and 
the ground drug, called Santonica (the true Levant wormseed), is exten- 
sively employed in stock remedies. 

It is evident that a great deal of Santonica is devoid of santonin, and 
that the drug as imported into the country may contain anywhere from 
3.5 per cent to nothing. It is not unlikely that the flowering tops of other 
species of Artemisia are shipped indiscriminately for Santonica. 

A. absinthium is the well-known wormwood, which is supposed to 
be one of the ingredients of absinthe. This species, as well as half a dozen 
others growing in this country, are employed as bitter tonics and stomachics 
and sometimes as emmenagogues, antiperiodics, diuretics, anthelmintics, 
etc. Nearly all of the Artemisias growing in North America are called 
wormwood, hence it would not be surprising if twenty or more different 
species were collected and marketed. A. absinthium contains thujone 
and absinthiin, the former a volatile ketone winch gives a characteristic 
property to the oil of wormwood, and the latter a bitter principle, perhaps 
of glucosidal nature. Of the other species we may mention A. abrotanum, 
southernwood, A. frigida, wild or mountain sage, A. pontica, Roman worm- 
wood (which must not be confused with Ambrosia artemisiaef olia) , A. 
vulgaris, mugwort or motherwort, and A. inert ellina, silky wormwood 
from the Alps and Central Europe. 

A. absinthium is the only one whose composition has received any 
attention, and the chemistry of that is in need of revision and amplification. 
While it is supposed to be used in the manufacture of the liqueur "Ab- 
sinthe," and the deleterious properties of the drink credited to its pres- 
ence, it is doubtful if a careful and sane investigation would sustain these 
convictions. The writer had occasion at one time to investigate samples 

391 



392 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

of all of the brands of Absinthe then being imported, as well as some of 
those made in this country, and as a result it appeared that in but one 
case was there any suggestion of a bitter principle resembling absinthiin, 
and the amount of thujone and oil of wormwood was in too small amount 
to yield any characteristic reaction. However, the ban was placed on 
imported " Absinthe " because it was deleterious to the health of the 
people of the United States, which it probably was because of its alcohol 
content, in the same way that all imported whiskies, wines, and cham- 
pagnes might be considered deleterious. 

Allusion was made above to Ambrosia artemisisefolia syn., A. elatior, 
which belongs to another family, the Ambrosiacea. This is the well- 
known Roman wormwood or ragweed of waste places and cultivated 
fields, and which is credited with being one of the aggravating causes of 
hay fever. Its extract has been recommended as a remedy for asthmatic 
conditions. A serum called Pollantin is prepared from the " serum 
toxin " of ragweed and is used locally in hay fever. 

There is another drug, Chenopodium or American wormseed, which 
can be considered to advantage with this group, both because of its use 
and the character of its active principle. The drug American wormseed 
is the fruit of Chenopodium ambrosioides (Chenopodiacese, Goosefoot 
family) (Syn. C. anthelminticum) . The fruit and oil distilled therefrom 
are official in the Pharmacopoeia. An extract of the drug is used in the 
preparation of combination worm remedies and laxatives for children and 
the oil, which consists largely of ascaridol, is a valuable vermifuge. 

To sum up the pharmacognosy of these paragraphs: 

Artemisia maritima and A. cina Levant wormseed: Santonica 

A. absinthium Wormwood Absinthe 

A. pontica Roman Wormwood (Not the common Roman 

wormwood of waste 
places and fields.) 
Ambrosia elatior syn. arte- Roman wormwood Ragweed 

misiafolia. 
Chenopodium ambrosioides American Wormseed 

syn. anthelminticum 

SANTONICA 

Santonica is used in the preparation of condition powders for stock. 
Its anthelmintic principle, santonin, is a popular remedy and is dispensed 
in tablet or lozenge form either by itself or in combination with calomel 
or podophyllin or both. 

The amount of santonin varies with the age of the bud and the individ- 
ual plant. It is supposed to be greatest just before the expansion of the 
flowers. For its determination in the drug the analyst is referred to page 
64. 



MISCELLANEOUS ACTING DRUGS 393 

Santonin, C15H18O3, crystallizes from dilute alcohol in pearly crystals, 
melting 171-172°. When dissolved in chloroform, the solvent on evapo- 
ration leaves a colorless syrup which crystallizes in feathery, frostlike 
radiating groups. When cautiously heated, santonin may be sublimed, 
but there is no danger of loss from drying at 100°. It gradually turns 
yellow on exposure to sunlight. 

Santonin is only slightly soluble in cold water, but is somewhat more 
soluble in boning water. It is fairly soluble in cold alcohol and ether and 
with ease in chloroform and boiling alcohol. It can be completely removed 
from an acid mixture by means of chloroform, but it is not removable by 
alkalies from its solution in organic solvents. It dissolves in alkalies, 
but the solution cannot be titrated to determine the santonin. 

Santonin is strongly lsevorotatory. (a) ^—173.8 for alcohol and 
— 171.4 for chloroform. It is neutral to litmus. 

Solutions of santonin are not precipitated by ordinary alkaloidal pre- 
cipitants, but the solid substance gives a few characteristic color tests. 
It dissolves in concentrated sulphuric acid with a yellow color, the isolated 
crystals being surrounded with a violet ring, as they join the solution; 
if this solution is then diluted with an equal volume of water and treated 
with ferric chloride a violet color is produced. Nitric acid produces no 
characteristic reaction, but on evaporating and adding alcoholic potash 
an intense orange color results. Santonin itself gives a red color with 
alcoholic potash. 

Santonin has the property of affecting the vision to such an extent tnat 
everything appears yellow. 

Santonin is the lactone of santoninic acid, C15H20O4, a derivative of 
naphthalene. The constitution of the lactone is probably 

CH 3 

I H 2 

0=C C CHCHCH3 

")>c=o 
/ 

H 2 C C CHO 

I H 2 

CH 3 

Santoninic acid may be obtained by treating santonin with alkalies, 
and after solution has taken place an excess of hydrochloric acid is added 
and the acid immediately shaken out with ether. It reverts to santonin 
if allowed to stand in contact with mineral acid, or when warmed to 120°. 
It crystallizes in rhombic crystals from alcohol and has an acid reaction. 



394 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Santonic acid, an isomer and much more stable than santoninic acid, is 
prepared by boiling santonin twelve hours with barium hydrate solution, 
acidifying with hydrochloric acid, and shaking out with ether. It forms 
rhombic crystals, melting 163°. 

Artemisin or oxysantonin, melting 202°, accompanies santonin in the 
drug. 

In analytical work it is not difficult to distinguish santonin from the 
other principles present in medicinal compounds. It is very sparingly 
soluble in acid aqueous solutions and may be separated from acid mixture 
with ease by chloroform. It is soluble in alcohol and crystallizes from 
dilute alcohol, melting 171-172°. Its color reactions are characteristic, 
and it gives negative tests with most of the reagents used for distinguish- 
ing the alkaloids and other commonly occuring substances. 

Determination of Santonin in Tablets. — Transfer 8 tablets to a small 
Squibb separator, and moisten with water (5 mils); add 2 drops dilute 
sulphuric acid. Shake out three times with 25-mil portions of chloroform, 
collecting each shake-out in another separator. Wash the combined 
chlorof ormic solutions with 5 mils of water, and when the water has entirely 
risen to the surface and no minute bubbles are seen through the mass of 
the liquid, run the chloroform into a tared beaker, through a pledget of 
absorbent cotton in the stem of the funnel. Evaporate the chloroform 
over the water-bath, using a fan, and when solvent has evaporated, dry 
for fifteen minutes in water oven. Weigh directly as santonin. 

With calomel present, the above procedure is not satisfactory, owing 
to the emulsifi cation which takes place when calomel, chloroform, and 
water are shaken together. The determination should be conducted in 
a 25-mil graduated cylinder with lip. Introduce 8 tablets and crush with 
a stout stirring rod. Add 20 mils chloroform and stir mixture with the 
rod. Filter the chloroform through a good grade of dry paper, free from 
pinholes, into a tared beaker. Repeat twice, then evaporate chloroform 
and finish determination as above. 

Calomel is insoluble in dry neutral chloroform. 

ABSINTHIIN AND ARTEMISIA 

Artemisia absinthium is used as a tonic and stomachic and it will 
sometimes be found in hniments mixed with menthol, oils of sassafras, 
calendula, and Echinacea angustifolia. 

Absinthiin is the bitter principle. It appears to be a glucoside, but 
its chemistry needs further study. The purified substance has been 
described as consisting of white inodorous crystals having the compo- 
sition C15H20O4, and melting 68°. It is reported as yielding dextrose 
on acid hydrolysis, and phloroglucinol when heated with alkali hydroxides. 

The chemist should not depend on this meager description for the 



MISCELLANEOUS ACTING DRUGS 



395 



characteristics of the bitter principle of wormwood. An extract of the 
true drug will always contain thujone, which lends itself much easier to 
detection, and whose properties are now well known. An acid aqueous 
solution obtained by digesting an evaporated alcoholic solution of worm- 
wood with water and acidulating, will yield a vitreous bitter residue to 
petroleum ether and to ether. Probably both of these residues contain 
absinthiin. 

If the chemist suspects the presence of this drug, a portion of the same 
should be distilled with steam and the distillate examined for thujone, 
while the residue is evaporated to dryness, extracted with alcohol, the 
alcoholic solution separated and evaporated and) the residue taken up 
with warm water which is then acidulated and shaken out with petroleum 
ether and with ether. If there is any appreciable quantity of the drug 
present in a medicinal compound it is recognizable by its odor, provided 
this is not masked by the aroma of high-scented flavoring oils. 

The test for thujone with sodium nitroprusside and acetic acid is of 
course a general reaction for ketones and ought not to be conclusive. 
Many other oils have been found to give the same reaction with sodium 
nitroprusside as oil of wormwood, namely, hyssop, calamus, verbena, 
and savine. 

ASCARIDOLE AND AMERICAN WORMSEED 

The drug known as American Wormseed consists of the fruit of Cheno- 
podium ambrosioides syn. anthelminticum. Its extract is employed as 
a worm remedy and is dispensed with extract of senna, Cascara sagrada, 
pumpkin seed, Rochelle salt and sodium bicarbonate in a class of medi- 
cines of the " Castoria " type, which are recommended as laxatives and 
worm expellants especially for children. The oil of Chenopodium is 
official in the Pharmacopoeia and consists of about 70 per cent of ascaridole, 
which seems to be the anthelmintic principle. Ascaridole will of course 
be found in the fluid extract. 

Ascaridole is an organic peroxide which has been assigned by Wallach 
the constitution 

CHa 



H 2 C 



H 2 C 



I 


I 



I 

C3H7 



CH 



CH 



396 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

It boils 96-97° under 8 mm. Specific gravity .9985 at 20° C. n D at 20° 
— 1.4769, sometimes slightly laworotatory, probably due to impurity. 
It is explosive when heated or when treated with concentrated mineral 
acids. On shaking with nearly saturated ferrous sulphate at a tempera- 
ture below 30°, a viscous product, ascaridol glycol, is obtained, which 
boils 271-272°. If the reaction is allowed to proceed without cooling, 
basic ferric sulphate will be precipitated and a combustible gas evolved. 
Ascaridole will not react with the reagents used to characterize the 
alcohols, ethers, ketones, aldehydes, and acids, but it is soluble in the 
ordinary organic solvents, and though it is present in the children's remedies 
in small quantity, its indifference to reagents will allow of its separation 
from other ingredients to such an extent that tests for its explosiveness 
can be applied. 

RAGWEED OR ROMAN WORMWOOD 

There are as yet no published data on the chemistry of Ambrosia 
elatior. The alcoholic extract has been used in conjunction with extract 
of Solidago species (golden rod) as a remedy for hay fever and asthma, 
but its application in this way is limited. 

Of late years it has been suggested that the plant gives off an albumen 
which has a toxic action on the mucous membrane. Based on this theory 
a serum has been prepared which when applied locally is stated to be of 
value in alleviating hay fever. 

Pollantin, Fall — Dunbar's Serum. — Antitoxic serum from horses 
treated with pollen toxin derived from ragweed. 

Horses are injected with gradually increased doses of pollen toxin 
(derived from ragweed), which results in the formation of an antitoxin 
after two or three months of treatment. The horses are then bled and 
the strength of the serum is estimated by determining the proportion which 
will prevent the action of a solution of pollen toxin, of which one drop is 
barely sufficient to produce a reaction when instilled into the conjunctival 
sac of a hay-fever patient. The serum is preserved by the addition of 
0.25 per cent of phenol. 

It is a clear, slightly yellowish liquid, having the odor and taste of a 
dilute solution of phenol. On standing, the liquid deposits a slight pre- 
cipitate. The liquid is alkaline in reaction and not irritating to the 
normal conjunctiva. 

Pollantin, Fall, has no pharmacologic action except the neutraliz- 
ation of the pollen toxin. The serum is not intended for use hypodermic- 
ally. It is employed for the relief of hay fever and it seems to be effective 
in a proportion of cases. It may be used as a prophylactic. 

Pollantin Powder, Fall. — A powder obtained by evaporating, in vacuo, 



MISCELLANEOUS ACTING DRUGS 397 

pollantin serum derived from ragweed toxin at about 45° C, and mixing 
it with sterilized sugar of milk. 

It is a fine, slightly yellowish, almost odoness powder, almost but 
not entirely soluble in water, and having a slight alkaline reaction. The 
tests are the same as for the liquid. It should reduce Fehling's solution. 

The powder is applied to the eyes by dusting on the conjunctiva and 
to the nose by snuffing into one nostril, the other being closed, a piece 
as large as a lentil. 

ASPmiUM 

The official drug called Malefern consists of the rhizome of Dryopteris 
Filix-mas syn. Aspidium Filix-mas (Polypodiacese) , true malefern, or of 
D. marginalis, evergreen wood-fern or marginal shield fern. 

The extract of this drug, or more commonly its oleoresin, is used in 
the removal of tape worm, and is usually administered with castor oil 
and kamala. 

Malefern oleoresin is often adulterated with castor oil. This prod- 
uct, which is also known as liquid extract of malefern, is of an oily con- 
sistency, obtained by an ether extraction of the drug. It has a specific 
gravity of 1.018-1.052, refractive index 1.4995-1.5157, saponification value 
227-259, unsaponifiable matter 4 to 7 per cent, material insoluble in 
petroleum ether 3 to 15 per cent, crude filicin 19 to 28 per cent, as deter- 
mined by the method of the Swiss Pharmacopoeia. The potash extract 
of oleoresin malefern is that portion of an ether solution of 20 grams 
soluble in 1 per cent potassium hydroxide. It contains acid constituents. 
The potash insoluble is that which remains in the ether and in genuine 
samples it amounts to about 50 per cent. The acid number of the potash 
insoluble portion is 28 to 36 in genuine samples but runs up as high as 
149 if castor oil is present. 

The Swiss method is as follows: 

Five grams of the extract are transierred to a 200-mil flask, 30 grams 
of ether added, followed by 100 grains of 3 per cent barium hydroxide, 
the whole well shaken, transferred to a separatory funnel, and allowed 
to stand ten minutes. The aqueous portion is filtered, 86 grams of the 
filtrate treated with 3 mils of hydrochloric acid, or sufficient to render it 
acid, and then shaken with 30-20-15 mil portions of ether. The com- 
bined ether extracts are filtered, the filter washed with ether, and the sol- 
vent solution evaporated in a tared dish, drying to constant weight at 
100° C. The residue should weigh 1.04 to 1.12 grams, corresponding 
to 26-28 per cent crude filicin in the extract, 



398 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

FILICIC ACID AND RELATED SUBSTANCES 

The most recent work indicates that Aspidium probably contains the 
following constituents, in approximately the amount indicated: Filicic 
acid, 3.5 per cent; flavaspidic acid, 2.5 per cent; albaspidin, 0.05 per 
cent; aspidinol, 0.10 per cent; flavaspidin, 0.10 per cent; amorphous 
acid, 5.0 per cent and filicic nigrine, 6.0 per cent. These substances are, 
for the greater part, derivatives of phloroglucinol, and some of them are 
ketones possessing acid characters. 

The various formulas assigned to the filicic acids and the different 
results reported regarding their physiological activity have given rise to 
much confusion, leaving the chemistry in an unsettled condition. One 
of the first formulas assigned to filicic acid is that of Luck — C26H30O9, 
which differs considerably from the formula C^HigOo — given this sub- 
stance by Grabowski, and C14H16O5, as suggested by Daccoma. Later 
two forms, a crystalline and an amorphous filicic acid, were recognized 
by Poulson, who suggested the formula, C36H40O12, for the crystalline 
filicic acid and C36H42O13 for the amorphous acid, which later he considered 
as the active therapeutic principle of aspidium. Poulson believed the 
crystalline acid to be the anydride of the amorphous acid. More recently, 
Gallas has stated the formula for both the crystalline and the amorphous 
filicic acid to be C18H22O6. Gallas and later Kraft concluded that one 
form of the acid was 'the lactone of the other form. Filicinic acid, which 
has the formula CgHieOs, is sometimes confused with filicic acid. Besides 
a difference in the theories regarding the constitution of the various filicic 
acids, there has been considerable controversy over the anthelmintic 
properties of these substances. 

Amorphous filicic acid is an organic acid, C36H42O13, obtained from 
several species of Aspidium. It is a white or yellow powder, without 
odor or taste, melting at 125° C., soluble in cold alcohol. 

Amorphous filicic acid has been recommended as an anthelmintic, 
and is generally considered one of the active principles of several species 
of Aspidium. It is usually combined with calomel and jalap. 

The crystalline filicic acid, also designated as filicinic acid, which is 
considered as an anhydride of the amorphous filicic acid, is devoid of 
anthelmintic action. 

Filmaron, C47H54O16, is an active anthelmintic constituent obtained 
from the ethereal extract of Aspidium. It has acid properties and occurs 
as a straw-colored amorphous powder, insoluble in water, difficultly 
soluble in ethyl and methyl alcohols and rather difficultly soluble in 
petroleum ether. It is readily soluble in all proportions of ether, acetic 
ether, amyl alcohol, chloroform, benzin, carbon disulphide, and acetone, 
and also, though with partial decomposition, in solutions of the alkalies 



MISCELLANEOUS ACTING DRUGS 399 

and alkali carbonates. The alcoholic solution exhibits a slightly acid 
reaction. Filmaron melts at about 60° C. It exhibits a strong tendency 
to cake together to form a resinous mass, which is difficult to reduce to 
powder and dispense; hence it is not marketed in substance, but as a 
10 per cent castor oil solution, which is known as " Filmaron oil." 

Five-tenths gram filmaron and 5 gram pumice stone, and 1 gram 
magnesia are finely triturated with 250 mils water, the mixture shaken 
for half an hour, and then filtered. On passing a rapid current of carbon 
dioxide through the filtrate a voluminous, flocculent precipitate forms; 
the filtrate should afford but very slight precipitate on the addition of 
hydrochloric acid. 

On dissolving 0.1 gram filmaron in 0.2 gram acetic ether or 0.2 gram 
carbon disulphide by rotation in a test-tube, and setting the stoppered 
tube aside for three days, no separation should have taken place at the 
end of this time (absence of other malefern constituents, filicic acid and 
flavaspidic acid). 

One-tenth gram filmaron should completely dissolve in 0.5 gram 
warm petroleum ether and leave no more than a slight trace of undissolved 
substance. To detect the filmaron in the castor oil solution (filmaron 
oil), dilute the filmaron oil with ether, shake out with sodium hydroxide 
solution, acidulate the alkaline liquid, and then take up the liberated 
filmaron with ether. On evaporating the ether and filmaron is obtained 
as a residue. 

PICROTOXIN 

The berries of Cocculus indicus or Anamirata paniculata (Menisper- 
macese), a small climbing shrub growing in India and the Malay Archi- 
pelago, contain a feebly acid principle, picrotoxin. Both the berries and 
purified picrotoxin are used medicinally in nervous disorders, where they 
exert a sedative action, and in phthisis to relieve night sweats. They 
are also employed externally to destroy parasites. Pills and hypodermic 
tablets of picrotoxin usually contain about A to sV grain. A decoction 
of the berries acts as a powerful fish poison and the fruit has received the 
name " fish berry." The practice of collecting fish by means of the fruit 
is not uncommon, and there are certain proprietary poisons which owe 
their efficacy to the presence of picrotoxin. 

The kernel contains the picrotoxin with picrotin and picrotoxinin. 
The shells contain alkaloidal substances to which the names menispermin 
and paramenispermin have been given. 

PICROTOXIN, C 30 H 3 4O 13 

Picrotoxin, when pure, is a colorless, shiny, prismatic crystalline sub- 
stance, bitter, odorless, permanent in the air, and melting at 200° C. 



400 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

It is sparingly soluble in cold water, but dissolves quite easily in hot 
aqueous solutions and in the presence of acids or alkalies. It dissolves 
easily in hot alcohol and benzol and less readily in chloroform and ether, 
and it may be removed from acid solutions by any of these immiscible 
solvents, but it cannot be extracted in the presence of alkalies. 

Treated with concentrated sulphuric acid, picrotoxin gives a yellow 
color, turning orange and becoming red on warming and gradually reddish- 
brown, while the solution becomes fluorescent, best observed by pouring 
the liquid into a narrow test-tube. A drop of a 20 per cent alcoholic 
solution of anisaldehyde added to a solution of picrotoxin in sulphuric 
acid produces a blue-violet ring, becoming blue. Evaporated with con- 
centrated nitric acid it leaves a reddish-yellow residue, which becomes 
red when moistened with aqueous alkali hydroxide. A solution in con- 
centrated sulphuric acid treated with potassium nitrate, gives a red to 
violet color when strong alkali hydroxide is added. A mixture of picro- 
toxin and sucrose becomes red on treatment with concentrated sulphuric 
acid. 

An aqueous solution of picrotoxin reduces Fehling's solution and 
ammoniacal silver oxide, but it gives no precipitate with neutral, or basic 
lead acetate, Mayer's reagent, gold, platinic, or mercuric chlorides, tannic 
acid, or most other general reagents for alkaloids. 

Picrotoxin is not a glucoside. It is decomposed by the action of 
hydrochloric acid into picrotin and picrotoxinin, both dilactones: 

C30H34O13 = C15H18O7+C15H16O6 

Picrotin Picrotoxinin 

The reaction also occurs when a solution in chloroform is allowed to stand, 
or when an aqueous or benzene solution is boiled. Both of the products 
of decomposition reduce Fehling's solution and ammoniacal silver oxide. 
Picrotin melts 245-250° and picrotoxinin at 200 C. 

Hydrolysis with aqueous alkali first gives alpha-pier otoxininic acid, 
C15H18O7, and beta-picrotinic acid, C15H22O9. These yield with excess 
alkali the dicarboxylic acids of picrotoxinin and picrotin, C15H20O8 and 
C15H22O9, respectively. These bodies, with the exception of alpha- 
picrotoxininic acid, do not reduce Fehling's solution or ammoniacal silver 
oxide. 

Picrotoxin is speedily decomposed when boiled with alkalies. 

The separation of picrotoxin from medicinal preparations is not dif- 
ficult. In the general scheme of analysis it will be found in greatest 
amount in the fraction obtained by shaking an acid aqueous solution with 
chloroform. It may be purified by dissolving in dilute ammonia, shak- 
ing out neutral substances with ether and chloroform, acidulating, and 
extracting with chloroform. The crystalline residue is then subjected to 



MISCELLANEOUS ACTING DRUGS 401 

the several color reactions, and a dilute aqueous solution may be added 
to a bowl containing a few small fish. The fish will soon begin to swim 
with uncertainty, lose their balance and ultimately rise to the surface, 
lying on their sides and frequently opening mouths and gill covers. 

Its estimation in pills and tablets may be accomplished by trans- 
ferring a sufficient quantity of the sample to a separatory funnel, dis- 
integrating with water, acidulating, and agitating with chloroform. Three 
or four extractions should be made and the combined extracts filtered 
into a tared beaker, evaporated, and weighed. 

CASPSICUM AND CAPSAICIN 

Capsaicin is the pungent principle of the fruit of Capsicum fastigiatum 
(Solanacese) , C. annuum, and other species of Capsicum, the former being 
by far the most pungent and furnishing the cayenne type of red pepper, 
to which medicinal Capsicum belongs, while the latter provides the paprika. 

Capsicum is administered both in the powdered form and as the oleo- 
resin in cases of enfeebled or languid digestion, dyspepsia, atonic gout, 
and colic, and externally as a rubefacient. It will be found in some 
liniment formulas, also in ointments and plasters and to a large extent 
in pills and tablets. It is also used to increase the pungency of ginger 
ales and a few other types of temperance beverages. 

Capsicum and myrrh are dispensed together in liquid form, and com- 
pound tincture of opium and chlorodyne formulas contain Capsicum. 
Among the great number of different pill and tablet combinations the 
following types may be mentioned, all of which often contain Capsicum; 
aloin, belladonna, strychnin, and Podophyllum resin; belladonna, Hyos- 
cyamus, Nux Vomica and Podophyllum resin; aloin, Nux Vomica, Podo- 
phyllum resin, colocynth comp. and croton oil; aloin, jalap resin, Podo- 
phyllum resin ; strychnin and Hyoscyamus ; aloes, gamboge, Podophyllum 
resin, and croton oil; aloin, jalap, and Podophyllum resin; gamboge, 
leptandra, Hyoscyamus, and oil of peppermint; belladonna, Nux Vomica, 
Cascara sagrada, Euonymus and Xanthoxylon; Podophyllum resin, Tar- 
axacum, Euonymus, Eupatorium, and Apocynum; Podophyllum resin, 
Hyoscyamus, Nux Vomica and mercury mass; the above formulas being 
of the cathartic type. 

Mixtures intended as fiver regulators will contain jalap and Podo- 
phyllum resins, Hyoscyamus and colocynth comp.; aloes, rhubarb, Podo- 
phyllum resin, and Hyoscyamus; Podophyllum resin, Nux Vomica, 
Leptandra, and Iris versicolor; jalap, and Podophyllum resin, Leptandra 
and gamboge; aloes, jalap, gamboge, Leptandra, Veratrum viride, croton 
oil, and calomel, sometimes with addition of Podophyllum and butter- 
nut. Stomachics and anti-dyspeptic tablets and pills will contain rhu- 



402 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

barb, Cinchona and Ignatia; rhubarb, strychnin, and ipecac; pepsin, 
Nux Vomica, and ipecac; pepsin, Nux Vomica, and charcoal; rhubarb, 
strychnin, ipecac, gentian, and sodium bicarbonate; gentian, mercury 
mass, ipecac, and strychnin; ginger, sodium salicylate, and cardamom; 
strychnin, ipecac, pepper, and gentian. Compounds intended for the 
relief of diarrhea and summer cholera consist of rhubarb, opium, camphor, 
and oil of peppermint; calomel, ipecac, morphin, and camphor; morphin, 
Cannabis sativa, nitroglycerin, Hyoscyamus, and oil of peppermint. 
Compounds for ague contain Gelsemium, Xanthoxylon, and cinchonidin; 
Nux Vomica, Hyoscyamus, and quinin; arsenous acid, cinchona alkaloids, 
eucalyptus, and iron ferrocyanide. Antiperiodic pills contain cinchonidin, 
ferrous sulphate, Podophyllum resin, strychnin, and Gelsemium. Cold 
tablets consist of quinin, aloin, calomel, aconite, ipecac, and opium; 
quinin, aloin, sodium bromide, acetanilid, and Cascara sagrada; and a 
formula for dipsomania contains quinin, arsenous acid, strychnin, and 
zinc oxide. 

The Capsicum species were originally confined to the American tropics, 
but they are now cultivated in all parts of the world. 

The characteristic constituent is a pungent substance, capsaicin, which 
is present to the amount of about .15 per cent. The drug also contains 
a small quantity of a non-pungent alkaloidal substance. Considerable 
oily material can be extracted by volatile solvents, and oleoresin of capsi- 
cum, which contains practically all of the capsaicin, is a well-known 
pharmaceutical product and is the form in which the drug is usually 
administered. 

Capsaicin crystallizes in pearly white leaflets melting 64 to 54.5°, 
but as ordinarily extracted in analytical work it is a colorless amorphous 
residue, often in such small quantity as to be invisible. It is intensely 
pungent, dilutions of one part in a million in water imparting perceptible 
warmth to the tongue and lips. It is soluble in the ordinary organic 
solvents and slightly in water, and is removed from aqueous mixtures by 
petroleum ether, hence in conducting analysis with the procedure of 
immiscible solvents, capsaicin is one of the first of the common substances 
encountered. 

Capsaicin has the probable composition, C18H27NO3, but it is not 
an alkaloid. It apparently contains a phenolic hydroxl and a methoxy 
group. Its alcoholic solution when treated with dilute ferric chloride, 
develops an evanescent greenish-blue color. An alcoholic solution acidu- 
lated with hydrochloric acid, and treated with a little platinic chloride 
develops an odor like vanilla when allowed to evaporate spontaneously. 
A solution of capsaicin in concentrated sulphuric acid develops a violet 
color on adding sugar. Nelson 1 has shown that it is a condensation 
1 J. Am. Chem. Soc, 1919, 41, 1115. 



MISCELLANEOUS ACTING DRUGS 403 

product of vanillyl amine (3-hychoxy-4-methoxybenzylaniine) and a 
decylenic acid: 

OCH3 
H0/~ NCH2NHCOC9H17 



The color, and odor reactions above described are of no value for detect- 
ing capsaicin in the ordinary run of medicinal preparations and beverages 
because of the comparatively small amount that is present in the quantity 
of the sample which can be sacrificed for analytical work. The only 
satisfactory method of detection is one based on its physiological action, 
and this must be conducted in such a way as to exclude the possibility 
of confusion with piperin and ginger principles. 

Lawall describes a method for detecting capsaicin which excludes the 
possibility of ginger bodies being present. 

If the sample contains alcohol add sufficient sodium hydroxide to 
render it slightly alkaline and then evaporate until the alcohol is expelled. 
Transfer the residue to a separatory funnel with water, acidify with sul- 
phuric acid and shake out with ether. Separate and evaporate the ether, 
add alcoholic potash to the residue, and heat for half an hour in a boiling 
water-bath under a reflux. Evaporate to dryness, take up the residue in 
water, and extract with ether. Separate ether extract and wash with 
water until the washings are neutral to litmus. Then allow ether to evapo- 
rate spontaneously in a dish. The tip of the tongue is then applied to 
the residue or to the center of the bottom of the dish where a residue would 
naturally concentrate when the presence of capsaicin will be apparent 
by its characteristic burning sensation. If but a minute amount is present 
it may take a few minutes for the reaction to develop, and in some cases 
it may be necessary to apply the entire residue to the tongue. 

Piperin, the alkaloid of pepper winch would appear in the same frac- 
tion as . capsaicin, is readily distinguished by means of its characteristic 
color tests. 

The comparative pungency of capsicum is determinable by physi- 
ological means. By True's method 1 a small weighed quantity of the 
powder is placed in a mortar with a small weighed quantity of cane sugar 
and triturated until the powders are completely mixed and reduced to 
great fineness. If on tasting a small portion of the powder, the sensa- 
tion of pungency is noted, further weighed quantities of sugar are added 
until the pungency can no longer be perceived. A ratio is thus established 
between the original weight of the capsicum used and the weight of the 
sugar necessary to bring the sensation of pungency just to the point of 
disappearance. 

1 Bulletin U. S. Dept. Agri. No. 43, Bu. Plant Industry. Dec. 16, 1913. 



404 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Scoville * proposes an analogous procedure, using an alcoholic extract 
of the drug. One gram of the powdered sample is macerated overnight 
with 100 mils of alcohol and after thorough shaking is filtered. The 
alcoholic solution is then added to sweetened water in definite proportions 
until a distinct but weak pungency is perceptible on the tongue. Pow- 
dered capsicums may run from 1-20,000 to 1-100,000, and oleoresin may 
test 1-150,000 and upwards. 

GINGER, 

Zinziber officinale (Scitaminese) possesses a pungent rhizome employed 
in dyspepsia, flatulent colic, and enfeebled conditions of the alimentary 
canal. It is an agreeable addition to bitter infusions and tonic mixtures, 
and is used to a large extent in remedies for diarrhea, dysentery, cholera 
morbus, colic, nausea, etc. 

Extract and tincture of ginger are popular household remedies. The 
oleoresin prepared similarly to the oleoresin of capsicum enters into the 
composition of pill and tablet formulas and is also used in the preparation 
of extracts for ginger ale. The powdered rhizome is combined with 
pancreatin, pepsin, and other digestives, and bismuth subcarbonate in 
popular remedies for impaired digestion which are sold in powder form. 

The pill and tablet formulas containing ginger are of the following 
type: aloes, ferrous sulphate, and Conium; aloin, Cascara sagrada, bella- 
donna, strychnin, and Podophyllum; Colocynth, jalap, gamboge, rhubarb, 
and calomel; cinchonidin, cardamom, gentian, pimento, pepsin, and 
hydrochloric acid; pepsin, pancreatin, and Nux Vomica; pepsin, pan- 
creatin, bismuth subnitrate, Nux Vomica, and sodium bicarbonate; 
sodium salicylate, Capsicum, and cardamom; aloes, ferrous sulphate, 
black hellebore, myrrh, soap, and canella (female pills); pepsin, char- 
coal, and magnesia (dyspepsia lozenges). 

Aromatic tincture N.F. contains ginger, cinnamon, cloves, cardamom, 
and galangal root. 

Ginger is obtained chiefly from India, the West Indies and certain 
parts of Africa. The Indian variety is known as black ginger and is 
prepared by scalding the cleansed root in boiling water and rapidly dry- 
ing it. In Jamaica the best roots are deprived of their epidermis and 
dried carefully in the sun, this variety being known as white ginger. The 
Indian variety is sometimes found coated with calcium carbonate or sul- 
phate, and again artificially bleached to simulate the white ginger from 
Jamaica. 

Ginger contains from 2.5 to 7 per cent of resinous material and fixed 
oil. Its flavor and characteristic odor depends on a volatile oil, and its 

1 J. Am. Pharm. Ass., 1, 453. 



MISCELLANEOUS ACTING DRUGS 



405 



pungency on the resinous constituents. The pungent principle has been 
isolated and is, like capsaicin, a derivative of vanillin, having the follow- 
ing composition: 

OCH3 

HO< 



>CH 2 CH 2 COCH3 



It is called Zinzerone by its discoverer, Nomura. 

Kraemer and Sindall * obtained the accompanying analytical data 
with authentic commercial samples of ginger from different sources: 





Total 
Ash 


Ash 

insol. in 

10 per 

cent HCI 


Cold 
H 2 

extract 


Volatile 

Ether 

Extract 


N on- vol. 
Ether 
Extract 


Alcoholic 
Extract 


Crude 
fiber 


Starch 


CaO 


African . . 


5.74 


1.15 


12.62 


7.17 


8.49 


7.20 


2.62 


55.07 


0.12 


Calcutta . 


7.47 


2.02 


14.20 


3.06 


6.50 


6.40 


5.46 


47.89 


0.13 


Calicut . . 


5.64 


0.55 


13,08 


4.62 


6.42 


7.76 


1.64 


48.77 


0.33 


Cochin . . . 


6.43 


0.85 


14.30 


7.03 


6.68 


8.04 


3.06 


52.00 


0.58 


Jamaica. . 


3.88 


0.45 


15.54 


3.23 


7.30 


5.80 


1.44 


58.97 


0.17 


Japan . . . 


6.16 


0.69 


14.40 


7.39 


7.01 


10.48 


1.60 


55.97 


1.68 



Kebler and Kimberly 2 found that Calcutta and Japanese gingers 
are not suitable for the preparation of the U. S. P. tincture, and that a 
properly prepared tincture should contain not less than 90 per cent -alcohol 
and from 1.25 to 1.75 per cent non-volatile matter. 

The presence of ginger in medicinal preparations is usually noticed 
by the aromatic vapors evolved on evaporating an alcoholic extract of 
the sample, and by the characteristic pungency of an aqueous decoction 
of the evaporated residue left by the alcohol. The absence of capsaicin 
may be determined by the procedure given under capsicum. 

In certain doubtful cases the actual identity of ginger may be desir- 
able. Seeker has suggested a method for accomplishing this: 

Dilute 10 mils of the extract to 30 mils, evaporate off 20 mils, decant 
into a separator and extract with an equal volume of ether. Evaporate 
the ether spontaneously in a porcelain dish and to the residue add 5 mils 
of 75 per cent sulphuric acid and about 5 mg. of vanillin. Allow to stand 
for fifteen minutes and add an equal volume of water; when in the pres- 
ence of ginger extract an azure-blue color develops. 

The actual value of this method is probably overestimated because 
it appears from recent work that certain hydrocarbon-like constituents 
of volatile oils will produce a similar if not an identical shade of color 
when subjected to the same procedure. Hence it would be advisable 

1 Am. J. Pharm., 80, 303. 

2 U. S. Dept. Agri. Bu. Chem. Bull., 152, 244. 



406 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

to consider with great caution any positive evidence as to the presence 
of ginger when based on this test alone. 

ASARUM CANADENSE. CANADA SNAKE-ROOT 

Asarum canadense (Aristolochiacese) , wild ginger, or Canada snake- 
root, possesses a pungent root stock. It is used medicinally as an aro- 
matic, stimulant, carminative, and diaphoretic. It is prescribed with 
Cinchona for certain forms of low fever. It is also combined with ipecac 
in syrupy mixtures. 

A. acuminatum and A. reflexum are eastern plants resembling the 
above species, and their roots might be mistaken for Canada snake-root 
by an inexperienced collector. 

Power examined the rhizome and found a volatile oil, resin, fat, an 
amorphous yellow coloring matter, uncrystallizable sugar, and a small 
quantity of a feebly basic principle. The volatile oil contained pinene, 
an isomer of borneol, asarol, which is perhaps identical with linalool, 
asarin a neutral substance, coeruline, and acetic and valeric esters of 
linalool. 

SERPENTARIA. VIRGINIA SNAKE-ROOT 

The rhizomes of both Aristolochia serpentaria and A. reticulata (Aris- 
tolochiacese) are official in the U. S. Pharmacopoeia as Serpentaria. As 
a drug it has stimulant, tonic, diaphoretic, and diuretic properties, and 
is often used in low fevers either by itself or combined with Cinchona 
alkaloids. It is also used in dyspepsia and as a gargle for sore throat. 
The extract has been at various times recommended as an emmenagogue 
and as a cure for snake bite. 

Virginia serpentaria, also known as serpentary, is found in rich dry 
woodlands from Connecticut to Michigan and southward. Texas ser- 
pentaria (A. reticulata) occurs in the Southwestern States, growing along 
river banks from Arkansas to Louisiana. 

The crude drug will often be found mixed with other root drugs, 
including Spigelia, senega, and abscess root (Polemonium reptens), the 
latter resembling serpentaria closely except that it is nearly white. 

Many other species of the genus Aristolochia of this countrv and of 
foreign habitat are used as drugs. 

The characteristic constituents of the rhizome appear to c 
a bitter principle and volatile oil containing pinene, and esters o 
which give the drug its camphoraceous odor and flavor. Ar 
has been reported from a species of Aristolochia from South 
but no basic substance has been isolated from the plant growi in the 
United States. 



MISCELLANEOUS ACTING DRUGS 407 

GLYCYRRHIZINIC ACID AND LICORICE ROOT 

Licorice root from Glycyrrhiza glabra and G. glandulifera (Fabacese) 
possesses a sweet principle which is employed for the purpose of masking 
the taste of other drugs, and the extract will be found in a great variety 
of medicinal compounds. As a drug, licorice is useful as an emollient 
and demulcent in coughs, catarrh, irritations of the bronchial and urinary 
organs, and other similar affections of the mucous surface. 

It will be found in fluid extract aloes compound; with aloes and myrrh; 
in black cohosh compound; rhubarb compound, various sarsaparilla 
compounds; in compound quinin elixirs, with glyceroles of eriodictyon, 
heroin, etc., elixirs of Cascara sagrada and Berberis aquifolium; Tar- 
axacum and wild cherry; eucalyptus, gentian; and many other bitter 
tonic compounds and bitter cough remedies. Aromatic elixir of glycyr- 
rhiza and syrup of glycyrrhiza are national formulary preparations. 

Compound licorice powder consists of powdered licorice root, senna, 
washed sulphur, sugar, and oil of fennel. Tully's powder consists of 
powdered licorice root, morphin sulphate, camphor, and calcium car- 
bonate. Brown mixture consists of extract of licorice, powdered opium 
benzoic acid, tartar emetic, camphor, and oil of anise. 

Among the tablet and lozenge formulas in which extract of Glycyr- 
rhiza functionates as a demulcent or emollient may be mentioned ammo- 
nium chloride and cubeb with and without codein; Conium and cubeb; 
benzoic acid, cubeb, and belladonna; ammonium chloride, tolu, cubeb, 
senega, ipecac, and Hyoscyamus; ammonium chloride, cubeb, and cocain; 
Krameria, bismuth subnitrate, and opium; cubeb, tolu, and Sassafras; 
coltsfoot, cubeb, peppermint, tolu, Capsicum, and oil of anise; pine tar, 
eriodictyon, senega, and wild cherry; and coltsfoot, acacia, horehound, 
wild cherry, tolu, anise, cubeb, and Capsicum. 

The commercial extract of glycyrrhiza or licorice paste is prepared 
by water extraction. It is a hard black mass, brittle, breaking with a 
shining fracture and almost entirely soluble in boiling water. Gums 
and resinous constituents are usually present and some varieties contain 
commercial glucose or corn syrup. This form is used almost entirely 
in the manufacture of chewing tobacco. 

The fluid and solid extracts of the Pharmacopoeia are prepared with 
ammonia and alcohol. Ammoniated glycyrrhizin is a scaly preparation 
of the sweet principle in the form of its ammonium salt. 

The important constituent of the root and extract is glycyrrhizic 
acid or gly^yrrjnzim^^It occurs in the root in soluble form, and by treat- 
ing the extract with a mineral acid the compound is broken up and the 
crude acid is precipitated as a brown resinous mass, difficultly soluble 
in water and especially when acidulated. When pure it forms colorless 



408 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

crystals, melting 195°. Chemically it is a diglucuronic ether of glycyr- 
rhetic acid and by Tschirch is accorded the structural formula: 



I I 

/OHC • CHOH— CHOH— CHO • CHOH • COOH 
C 3 iH450 3 ^-COOH 

\OHC ■ CHOH— CHOH— CHO— CHOH • COOH 

I I 



Housemann 1 reports that glycyrrhizinic acid contains nitrogen. In 
his investigation he evaporated a solution of the acid to dryness in vacuo, 
crystallized the residue twice from hot glacial acetic acid, and finally 
dried over potassium hydroxide in vacuo. Analysis of the product showed 
58.37 per cent carbon, 7.72 per cent hydrogen, 1.09 per cent nitrogen. 
Three recrystallizations from glacial acetic acid raised the nitrogen to 
1.89 per cent. The substance turned brown at 185° and partly melted 
with frothing at 203-205°. It was readily soluble in hot water, the solu- 
tion gelatinizing on cooling. 

Housemann found 2 per cent of sucrose in the root. The inner bark 
of both green and dried root, but not the outer bark or central part of 
the root, contain hemolytically active saponins, in addition to the saponi- 
genin glycyrrhetic acid. These are extracted by 75 per cent alcohol but 
not by water or by alcohol weaker than 50 per cent. 

Properly purified glycyrrhizin at a dilution of 1-20,000 has a lasting 
pure sweet taste. 

In the analysis of medicinal products, glycyrrhizinic acid will appear 
when an evaporated alcoholic extract of the sample has been treated 
with water, filtered from any resinous constituents, and then treated with 
dilute sulphuric acid previous to shaking out with immiscible solvents. 
The appearance of a brown, resinous precipitate at this point is strongly 
indicative of glycyrrhizinic acid. It usually sticks to the side of the con- 
tainer and the liquid is readily decanted, the substance washed with ice 
water, or very dilute acid and then dissolved in ammonia and the filtered 
solution evaporated. The residue, which will have a scaly appearance, 
is soluble in water and the solution has a characteristic sweet taste. 

Housemann 2 recommends the following procedure for the analysis 
of licorice paste: 

Moisture and ash are determined in the usual manner. 

Matters Insoluble in Cold Water. — Two grams of the extract are 
spread on the sides of a small, copper gauze basket, which is placed in 
a 100-mil cylindrical glass tube drawn out to a conical end and contain- 
ing about 75 mils of distilled water. The tube is closed with a rubber 
stopper and agitated in a shaking machine until the paste is completely 
1 Amer. J. Pharm., 1916, 88, 97. 2 Amer. J. Pharm., 84, 1912, 531. 



MISCELLANEOUS ACTING DRUGS 409 

disintegrated (one-half hour to one hour) and then whirled in a Babcock 
centrifuge for fifteen minutes at 1000 revolutions per minute. The 
clear liquor is poured off and the sediment stirred up with fresh water 
and whirled for a further fifteen minutes. After pouring off the liquor, 
the sediment is washed into a tared glass dish, evaporated and weighed. 

Most licorice pastes, when freshly made, will contain not more than 
3 per cent by weight of matters insoluble in cold water, unless made from 
very starchy root or from liquor which, having been partly chilled, con- 
tains gelatinized starch. A paste containing more than this amount 
should be dissolved without the aid of a shaking machine by suspending 
in cold water, as the use of the shaking machine is found to give low results 
with pastes containing much insoluble matter. Many experiments have 
shown that fifteen minutes is a sufficient time to centrifuge at 1000 revo- 
lutions, the results being identical with those obtained by twenty-four 
hours settling in a tall jar. 

Matters Insoluble in Hot Water. — This estimation is carried out in 
a similar manner to the preceding determination, using hot water. 

Starch and Gums. — Two grams of licorice mass are dissolved in 10 mils 
hot water, in a centrifuge tube similar to that used for " matters insol- 
uble in cold water." The solution is cooled and 20 mils 80 per cent alco- 
hol (by volume) are added with stirring. Fifty mils 95 per cent alcohol 
are then added gradually with stirring. After allowing to stand two 
hours, which time is found sufficient to precipitate all starch and gummy 
matters, the contents of the tube are centrifuged. After pouring off the 
clear liquor, the precipitate is stirred up with 80 per cent alcohol and 
centrifuged. This operation is carried out three times in all. The pre- 
cipitate, consisting of starch and gums, and the mechanical impurity in 
the paste, is washed into a tared dish, evaporated, and weighed. The 
mechanical impurities (matters insoluble in hot water) are deducted, to 
give the true weight of starch and gums. 

Glycyrrhizin. — The clear 80 per cent alcoholic liquor, poured off from 
the starch and gums, is evaporated just to dryness in vacuo on a water- 
bath. The residue is transferred to a small conical beaker with 30 mils 
water and after cooling to 15° C, the crude glycyrrhizin is precipitated 
with 3 mils dilute sulphuric acid (10 mils cone, sulphuric acid to 300 mils 
water). After standing for two hours (twelve to twenty-four hours, as 
usually recommended, is unnecessary and gives lower results) at a tem- 
perature of about 10° C, the contents of the beaker are cooled in ice 
for half an hour, and the clear supernatant liquor poured through a small 
filter. The glycyrrhizin is washed four times by decantation with ice 
water, in which it is practically insoluble. The glycyrrhizin in the beaker, 
together with any that may have beeen transferred to the paper, is dis- 
solved in dilute alcohol. Two drops of 5 per cent ammonia are added 



410 GLUCOSIDES GLUCOSIDAL DRUGS AND NATURAL DRUGS 

to neutralize traces of sulphuric acid, and the solution is transferred 
to a tared dish, evaporated, and the crude glycyrrhizin weighed. 

Sugars. — The filtrate and washings from the glycyrrhizin, amount- 
ing to about 70 mils, are received in a 100-mil graduated flask. Enough 
of a concentrated solution of basic lead acetate is added to precipitate 
both the sulphuric acid and the resins, bitter substances, coloring matters, 
etc. (3 mils are usually sufficient). The liquid is made up to 100 mils 
and an aliquot filtered into a 100-mil graduated cylinder. The excess 
of lead is exactly removed with sodium carbonate, the liquid made up to 
100 mils again, filtered, and titrated with Fehling's solution before and 
after inversion. 

The method for the determination of glycyrrhizin can be used to 
advantage in estimating that substance in commercial ammonium glycyr- 

COMPOUND LICORICE POWDER 

The moisture and ash can be estimated by the ordinary methods. 
Glycyrrhizin, sugar, and water-soluble extract are determined by digest- 
ing 5 grams of the sample with 250 mils of water for twenty-four hours 
with occasional agitation. After settling, aliquots of 50 mils each are 
used for the water soluble extract and sugar determinations, and 100 mils 
for the glycyrrhizin. The technique to be employed in estimating glycyr- 
rhizin is the same as in licorice paste. 

The total sulphur is determined by oxidizing 1 gram of the powder 
with fuming nitric acid and a little potassium nitrate or chlorate, and 
finally precipitating with barium chloride. 

The anthraquinone derivatives of the senna can be estimated by the 
method described on page 62. 

Parkes and Major 1 who outlined a procedure essentially like this 
one examined 13 samples of compound licorice powder and obtained the 
following data: moisture 3-7.9 per cent; ash 4.6-6.2 per cent; water 
extract 61.1-63.9 per cent; sucrose 48.3-50.3 per cent; glycyrrhizin 
1.2-2.9 per cent; total sulphur 7.8-9.2 per cent. 

Tschirch and Gauchmann report the presence of glycyrrhizinic acid 
in the root of Periandra dulcis and the bark of Pradosia lactescens, both 
from Brazil. 

Eupatorium rebaudianum contains two sweet principles of the nature 
of glucosides. They have been separated by dissolving in methyl alcohol 
and pouring into absolute alcohol, which precipitates rebaudin and leaves 
eupatorin in solution. The former is soluble in water, methyl alcohol, 
and dilute acids, but insoluble in ethyl alcohol and ether. The latter 
is soluble in water, methyl and ethyl alcohols, and acids, but insoluble 
in ether. They are therefore essentially different from glycyrrhizinic acid. 
1 Analyst, 1914, 39, 160. 



MISCELLANEOUS ACTING DRUGS 411 

This eupatorin must not be confused with the substance of the same 

name which has been extracted from Eupatorium perfoliatum or common 

boneset. 

CANTHARTDES AND CANTHARIDIN 

Cantharidin occurs in the anatomy of a number of insects. The 
species Cantharis versicatoria is official in our Pharmacopoeia. If kept 
• perfectly dry the activity is retained for a long time, but it is subject 
to the attack of a small worm which consumes the interior parts, and 
the vesicating power is lessened to a considerable degree by the attack 
of this pest. 

Some of the other species of insects containing cantharidin include 
Mylabris oculata, Thunb; M. holocericia, Kley; Decatonia lunata, 
Pallas; Electica wahlborgia, Fabr; Cantharis vellata; Lytta ccelestina; 
Cantharis vittata; C. cimeria; C. marginata; C. atrata; C. vulnerata 
and others. 

Cantharides as a drug is used principally in remedies for the stimu- 
lation of the urinary and genital organs, in hair tonics, and locally for 
blistering purposes. It is reported to be of value in producing sexual 
excitement. 

It is often combined with phosphorus, Nux Vomica, damiana, and 
zinc phosphide; with belladonna, saw palmetto, and corn-silk; and 
with guaiac, aloes, and ferrous sulphate. Cantharidal collodion is a 
pharmacopceial preparation of this drug which furnishes a ready medium 
for the exhibition of its vesicating properties. 

Cantharidin occurs partly free and partly combined and the nature 
of the combination is unknown. It is volatile on evaporation with sol- 
vents, but can be dried at 60° for two hours without loss. It is fairly 
soluble in acetone, chloroform, and ethyl acetate, moderately in alcohol, 
ether, and hot water, but only very slightly in cold water and petroleum 
ether. 

Cantharidin forms colorless, shining, neutral, rhombic leaflets, melt- 
ing 218°, and subliming at higher temperatures in white needles. 

It is a monobasic acid and a /5-lactone. Potassium or sodium hydroxide 
break the labile /3-lactone ring, and by this means cantharidin forms the 
alkali salt of dibasic cantharidic acid. 

H H 

/?\/ CHC00H /?\ /CH 2 -COOK 

H 2 C C— O H 2 C 

+ 2KOH = 



CH 



CH 2 ] 

\l 
H 2 C C— C=0 H 2 C C— COOK 

\c/ \c/ 

H 2 H 2 



0H +H 2 



412 GLYCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

These alkaline salts are crystalline and on treatment with a mineral 
acid cantharidinic acid is set free, which soon loses a molecule of water 
and passes into cantharidin. The alkali cantharidinates are used medi- 
cinally as remedies for phthisis. 

In the general scheme of qualitative analysis of medicinal preparations 
cantharidin will, in part, be found in the aqueous solutions of the evapo- 
rated alcoholic extract of the mixture from which it will be separated 
in the ether fraction. As it gives no characteristic color resctions and 
as it is in such small quantity usually that a melting-point determination 
is impossible, it is necessary to resort to a physiological reaction which 
depends on its vesicatory power. For this purpose the residue is dissolved 
in chloroform and the solution applied drop by drop to the under side 
of the forearm above the wrist. As each drop evaporates another is 
applied in the same spot. If any cantharidin is present the tingling effect 
will soon be apparent and the blister will appear. 

Assay of Cantharides. — Twenty grams of cantharides, in fine powder, 
are moistened with 3 mils of strong hydrochloric acid, and extracted, 
in a Soxhlet apparatus, with 80 mils of benzene for two hours. The 
residue is washed with 25 mils of benzene, and the benzene removed from 
the extract by distillation and, finally, by a current of air. The distilled 
benzene is shaken with successive portions of 20 mils, 20 mils, and 10 
mils of a 1 per cent solution of potassium hydroxide to recover any traces 
of cantharidin which have distilled over, and the mixed alkaline solu- 
tion is acidulated with hydrochloric acid, made up to 105 mils with dis- 
tilled water, and added to the residue of fat and cantharidin left after 
distilling off the benzene. The mixture is boiled for ten minutes under 
a reflux condenser, and so soon as the layer of fat has separated, 100 mils 
of the hot aqueous layer are pipetted off. The boiling is then repeated 
four times for five minutes after addition each time of 50 mils of distilled 
water, 50 mils of the separated aqueous layer being removed after each 
boiling. The mixed aqueous solution is acidified with 3 mils of strong 
hydrochloric acid, and shaken with successive portions of 30, 30, 
20, and 20 mils of chloroform. The chloroform extract is distilled 
in a tared flask, the residue washed with quantities of 5, 5, and 
2 mils of a mixture of equal parts of absolute alcohol and petroleum spirits 
saturated with cantharidin, and the cantharidin dried at 60-65° C. until 
of constant weight. 

DETERMINATION OF CANTHARIDIN IN TINCTURE, OIL AND PLASTER OF 

CANTHARIDES 

Tincture. — Fifty grams of the tincture, 25 grams of water, and 1 mil 
of sodium carbonate solution (1:2) are evaporated tog-ether to dryness 



MISCELLANEOUS ACTING DRUGS 413 

on the water-bath. The residue is taken up with 10 mils of water, 
treated with 2 mils of hydrochloric acid (1:4), and shaken out with 10 
mils of chloroform, which has been used previously to rinse out the flask. 
After separation, the chloroform is drawn off, and the acid aqueous liquid 
is again shaken out with 5, 5, and 5 mils of chloroform in succession. The 
chloroform extract is evaporated at a gentle heat, the last traces of sol- 
vent being blown off with an air current. After standing for twelve 
hours, the air-dried residue is treated once with 10 mils, then four times 
successively with 5 mils of light petroleum spirits. These petroleum 
spirit washings are passed through a small filter. The air-dried residue 
and this filter are then washed, first with 10 mils of water containing a 
drop of ammonium carbonate solution, then with pure water, and dried 
at 50° C. The dry residue is dissolved in a little acetone, and passed 
through the dry filter, into a small tared flask. The solvent is evapo- 
rated off at a gentle heat by the aid of a current of air, and the brownish- 
yellow residue is dried, first at 50° C. and finally in the water oven, till 
of a constant weight. 




CHAPTER XIII 
BOTANICAL DRUGS 

WHITE PINE 

The inner bark of the white pine, Pinus strobus (Pinacese), is used 
as an expectorant and is one of the ingredients of white-pine syrup. The 
extract of the drug is usually combined with several of the following: 
wild cherry, balsam poplar buds, spikenard, Sanguinaria, sassafras, squill, 
senega, ipecac, opium, camphor, morphin, chloroform, methyl salicylate, 
potassium nitrate, glycerin, codein, Cannabis sativa, Eriodictyon, ammo- 
nium chloride, tar, tolu, and honey. 

Compound syrup of white-pine contains white-pine, wild cherry bark, 
balsam poplar buds, spikenard, Sanguinaria, sassafras, morphin, and 
chloroform. 

Coniferin, Ci 6 H 2 20 8 -l2H 2 

Coniferin occurs in the cambium sap of coniferous trees. It forms 
white satiny needles with two molecules of water of crystallization, efflores- 
cing in dry air and becoming anhydrous at 100°, melting at 185°. It 
is soluble in alcohol and slightly in hot water, insoluble in cold water and 
ether. The aqueous solution has a bitter taste and is laevorotatory 
(<x)d — —66.9°. It dissolves in concentrated sulphuric acid with a red 
color, a deep blue resinous substance separating on dilution with water. 
When moistened with carbolic acid and treated with concentrated sul- 
phuric or hydrochloric acid, it rapidly acquires a deep-blue color. It 
gives no reaction with metals nor Fehling's solution. 

Coniferin is oxidized to vanillin when warmed with chromic acid. 
Emulsin hydrolyzes it to coniferyl alcohol and dextrose, but when dilute 
acids are employed the coniferyl alcohol polymerizes or resinifies. 



Coniferyl Alcohol. C 6 H 3 -OCH 3 - OH- C 3 H 4 OH -3.2.1 

Coniferyl alcohol melts 73-74°, soluble in alcohol, ether, and alkalies, 
with difficulty in water. It is reduced by sodium amalgam to eugenol, 
and oxidized by chromic acid to vanillin. 

414 



BOTANICAL DRUGS 415 

TRITICUM. COUCH-GRASS. DOGGRASS 

The rhizome of Agropyron repens (Graminse) furnishes the commercial 
triticum. It is chiefly employed in kidney troubles, and its presence 
may be suspected in any mixture recommended for cystitis and irritable 
conditions of the bladder. It is usually combined with one or more of 
the following: buchu, Hydrangea, corn silk, pichi, Viburnum prunifolum, 
atropin, borates, potassium bicarbonate, and benzoic acid. 

No examination has been made of the constituents of this drug. If 
it is suspected in a mixture, the sample should be diluted with water, 
centrifuged and any vegetable residue at the bottom of the tube care- 
fully examined under the microscope for the presence of characteristic 
tissue. 

SAW PALMETTO 

The ripe drupe of Sabal serrulata syn., Serenoa serrulata (Palmse), a 
small palm growing in sandy soil in the Southeastern States, furnishes 
the drug. 

Saw palmetto is considered valuable in a variety of conditions and 
may be found in tonics, remedies for diseases of the mucous membrane 
of the nose and throat, and for abnormal and irritated conditions of the 
urinary tract, and the organs of generation. It is combined with can- 
tharides, belladonna, and corn silk; with Nux Vomica; with coca, kola, 
and Apium graveolens; with santalwood oil, and with olive oil. 

The fresh fruit contains a volatile oil, and there is present in the drug 
a green or brownish fixed oil, consisting of the esters of a number of fatty 
acids including caproic, caprylic, capric, lauric, palmitic, and oleic. Resins 
and glucose are present. 

Mann, 1 who has done some phytochemical work with this drug, con- 
cludes that the so-ca led volatile oil which is contained in the alcoholic 
extract is not a volatile oil in the generally accepted sense of the term, 
but a mixture of ethyl esters of fatty acids, formed by condensation of 
the free fatty acids, which are naturally contained in the berries, with 
alcohol. 

IRIS VERSICOLOR AND IRIS FLORENTINA 

There are some twenty-one species of Iris growing in North America, 
but only one of these, Iris versicolor (Iridaceae), the larger blue-flag, has 
been used as a drug. The root is the portion employed, and while the 
therapeutic value of the freshly gathered material appears well established, 
the activity is apparently lost on standing, and much of the material that 
is sold on the market is probably inert. 

1 Amer. J. Pharm., 1916, 88, 517. 



416 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The extract of the rhizome and roots and a more or less purified form 
of the resinous constituents in the character of a concentration termed 
Irisin or Iridin, are the ordinary forms in which Iris is administered. In 
liquid preparations Iris occurs with Stillingia, Bicuculla canadensis, Chim- 
aphila, Sambucus canadensis, Xanthoxylum berries, and coriander (Still- 
ingia compound; with Stillingia, Bicuculla, Xanthoxylum bark, and 
potassium iodide; these preparations being designed for alterative and 
chologogue purposes. Iris is credited with great efficiency in liver com- 
plaints and hence is often combined with Podophyllum resin. In pills 
and tablets it occurs with Podophyllum, Nux Vomica, Capsicum, and 
Veronica virginica; with Podophyllum and strychnin; with Podophyllum, 
Hyoscyamus, and strychnin; with Podophyllum, Sanguinaria, and Euony- 
mus; with Xanthoxylum, Stillingia, Arctium lappa, Phytolacca, and red 
clover blossoms. 

Power and Salway * examined a commercial sample of Iris versicolor, 
finding it free of basic or glucosidal constituents, and in an aqueous decoc- 
tion of the alcoholic extract, identified isophthalic acid, salicylic acid, tan- 
nin, and sugar yielding a c?-phenylglucosone, melting 212°. The portion 
of the alcoholic extract insoluble in water consisted principally of a soft 
dark resin which amounted to about 8.7 per cent of the weight of the 
drug. From it were separated a phytosterol, C27H46O+H2O, melting 
when anhydrous, 148° (a)z>= —35.6°, in chloroform, myricyl alcohol, 
heptacosane, C27H56, ipuranol and a mixture of lauric, palmitic, stearic, 
cerotic, oleic, and linolic acids. 

IRIS FLORENTINA 

The root of I. florentina, the white flag or orris, was formerly employed 
as a cathartic and emetic, but at present finds its chief use in dentifrices, 
bath, toilet, and hair powders. It has a limited use in surgical work because 
of its great absorptive power. 

Orris root contains a large percentage of starch and 0.1-0.2 per cent 
of volatile oil, which consists chiefly of myristic acid, with a ketone to 
which the name irone (ionone?) has been given, and to which the odor 
of the root is due. The odor of the pure ketone is pungent, and in the 
concentrated form seems to differ entirely from that of the violet, but 
the violet aroma becomes apparent when irone is dissolved in a large 
amount of alcohol and the solution evaporated. 

CROCUS SATIVUS. SAFFRON 

Crocus sativus (Iridacese) furnishes a drug closely allied to those just 
mentioned. It was formerly used as an antispasmodic and narcotic 

1 Amer. J. Pharm., 1911, 83, 1. 



BOTANICAL DRUGS 417 

emmenagogue, but is now mainly a coloring and flavoring agent. It is 
still a component of pills containing aloes, myrrh, rue, and savine; of 
Warburg's Tincture; and of some Cinchona preparations. 

Its high price has made it an attractive subject for adulteration, and 
though its importance as a drug is slight, much attention has been devoted 
to suppressing the traffic in the adulterated product. 

The plant is perennial, rising from a conn, the flowers being lilac- 
purple with orange-red stigmas, which furnish the article known commer- 
cially as saffron. It should not contain the yellow styles. Dried saffron 
has about 7.5 per cent ash. When chewed it imparts an orange-red color 
to the saliva. 

It contains a volatile oil. To water it yields, among others, a yellow 
substance to which the name crocin has been given. The yellow sub- 
stance is also soluble in dilute alcohol, but only slightly in absolute alcohol. 

The adulterants include the florets of species of composite, Calendula, 
Carthamus, and Arnica, fixed oils, glycerin, mineral matter, exhausted 
saffron dyed with coal-tar colors, and factitious products of which " Fem- 
inella " is a type, and consisting of florets of Calendula or other flowers 
colored to imitate the characteristic shade of saffron. 

Vicari 1 recommends the use of sulphomolybdate reagent (60 mils 
cone, sulphuric acid and 40 mils 10 per cent sodium phosphomolybdate) 
for detecting Carthamus in saffron. The powder is spread over a glass 
slide in a thin coating without lumps. A drop of the reagent is allowed 
to fall upon the powder and well mixed with it. A greenish-blue color 
soon develops and then a cover glass is gently pressed down on the slide. 
Under a microscope of 50 diam. magnification, the particles of Carthamus 
are detected by their reddish color in the midst of the blue particles of 
saffron. If the particles of saffron are somewhat voluminous, or if the 
preparation of the powder for the microscope is not properly done, the 
coloration may be masked. An indication of the presence of Carthamus 
is furnished by observation under the microscope (100 diameters magni- 
fication) of the pollen grains. These are composed of two membranes, 
the outer being hard, resistant, and granulated exteriorly, the inner soft 
and delicate, and filled with a relatively dense, hyaline, protoplasmic 
liquid. The outer membrane is pierced with three symmetrically arranged 
openings, through which the inner issues, forming three typical protuber- 
ances. Under the microscope and in the presence of the reagent the outer 
membrane becomes colored brown, while the protuberances gradually 
elongate, turn a bright greenish blue, and finally take on sac-like forma- 
tions, on account of the endosmosis of the reagent through the membrane 
increasing the tension of the internal protoplasmic substance. In time 
the reagent attacks the outer membrane, exposing to view its structure, 
1 Mitt. Lebens. Hyg., 1915, 6, 195. 



418 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

thickness, and granulation. Sometimes the complete inner membrane 
will break intact through the weakened outer. The pollen grains of saf- 
fron under the action of the reagent merely turn blue, without modifica- 
tion or swelling. 

MATICO 

The constituents of matico reported by recent investigations as occur- 
ring in the drug differ considerably from those which were reported when 
it first came into use as a medicine. This may be due to the fact that 
different species figure in the investigations, or that changed con- 
ditions of climate, environment, or source have altered the characteristic 
components. 

The official drug is supposed to be the leaf of Piper angustifoHum 
(Piperacese) , and according to Thorns it is hard to find this leaf in a pure, 
unadulterated condition. Some consignments often consist of P. lineatum 
either in whole or in part, and these are sometimes admixed with unidenti- 
fied leaves. 

Dr. Rusby states that the plant producing matico is a native of the 
Andes of Peru and Bolivia; the so-called matico plants of Mexico, Brazil, 
and other sections are different species. At one time all of the shipments 
of matico offered for import were of P. mandonii, and had a much weaker 
odor and taste than the genuine. 

In tropical America the term " matico " is applied to a number of 
astringent and hemostatic leaves, several of which are from species of 
Piper, and of importance in commerce. These include P. aduncum, P. 
camphoriferum, P. angustifoHum var ossanum, P. acutifolium subver- 
bascifohum, P. mollicomum, and P. asperifolium. 

In looking up the history of this drug an interesting story is found to 
be connected with it, though it must be taken with reserve, as it has been 
applied to other vulneraries of tropical America. According to the legend 
the name " Matico " was first applied by the inhabitants of Quito to 
Eupatorium glutinosum, the properties of which were discovered by a 
soldier called Mateo, better known under the name of Matico (little Mat- 
thew), who, wounded in action, applied the leaves with good effect in 
stopping bleeding. Another plant, Waltheria glomerata, possessing similar 
properties, has obtained the name Matico in the Panama region, where 
it is also knowm as Pado-del-soldado (Soldier's tree), and a story similar 
to that given above is connected with it. 

It is interesting to note that E. glutinosum sometimes occurs in ship- 
ments of matico and is now considered an adulterant. 

Matico occurs in remedies for diseases of the genito-urinary organs, 
and is usually administered in the form of an oleoresin, combined with 
copaiba, cubeb, and santalwood oil. It is also used to treat bronchial 



BOTANICAL DRUGS 419 

affections, chronic diarrhea, and hemorrhage of the lungs, kidneys, and 
gastro-intestinal tract. Its extract is found in elixirs with Hydrangea 
and Uva Ursi. 

Maticos at one time yielded an oil which contained a product to which 
the name " Matico camphor " was given. This product does not appear 
in the distillates from any of the maticos at present on the market. Schim- 
mel finds that there are marked differences in the products of distillation 
from different lots of matico, even though there may be little difference 
in the odor and appearance of the drug. Scnimmel never finds matico 
camphor, but does get asarone and often methyl eugenol. 

Thorns reports the following characteristics of oils from different species 
of Piper which have been found in matico shipments: 

Oil from P. angustifolium of undoubted origin contained parsley apiol, 
dill apiol, a hydrocarbon boiling 121-130° under 13 mm., and a small 
amount of a phenol ether. Neither matico camphor nor asarone were 
found. Dill apiol is l-allyl-5-6-dimethoxy-3-4-methylene dioxy-benzene. 

Oil from P. camphoriferum (DeCandolle) has specific gravity .9500, 
(a) D =+19° 21' and contained camphor, borneol, terpenes and sesquiter- 
penes. 

Oil from P. lineatum had specific gravity .958, rotation +8° 45', and 
contained a large quantity of sesquiterpene but no camphor. 

Oil from a variety styled P. angustifolium var. ossanum yielded a 
camphor mixture. 

The properties reported for matico camphor by Kugler in 1885 showed 
it to have a melting-point of 94° C. and devoid of odor and taste. The 
impure substance possessed the characteristic odor of the drug and melted 
89-103°. Matico camphor floats on water with a rotatory motion. It 
is soluble in alcohol, ether, chloroform, and benzol, and is not attacked 
by alkalies. With sulphuric acid it gives a yellow color, changing to red 
and violet; with a mixture of sulphuric and nitric acids it gives a yellow 
changing to violet and blue. Hydrochloric acid produces a violet color, 
changing to blue and green, the compound yielding brown crystals with 
ether, which have an ethereal odor and show a green fluorescence. 

Besides the volatile oil the matico leaf contains tannin, resinous con- 
stituents, and an acid which has been called artanthic acid, 

CUBEB 

The fruit of the cubeb contains substances of reputed value for the 
relief of diseased mucous membranes, and preparations containing the 
extract or the oleoresin are widely used for gonorrhea, gleet, and catarrhal 
inflammation of the urinary and other mucous tracts. The drug con- 
sists of the full-grown unripe fruits of Piper cubeba (Piperacese). 



420 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The oleoresin, which is an evaporated ethereal extract of the drug, is 
combined with copaiba alone and with other substances such as santal- 
wood oil, turpentine, oleoresin matico, extract of buchu, extract of 
Krameria, iron chloride, salol, and pepsin; salol, pepsin, santalwood oil, 
and olive oil. Oil of cubeb is sometimes substituted for the oleoresin, 
and in pills and tablets we find copaiba and cubeb combined with guaiac 
and ferric citrate; turpentine and ferrous sulphate; santalwood oil, etc. 
Cubeb, either in the oleoresin, extract or powdered form, is also com- 
bined in pills and tablets with ferrous sulphate and Krameria; with lico- 
rice and ammonium chloride, sometimes with codein; with licorice and 
Conium maculatum; with licorice, ammonium chloride, tolu, ipecac, 
senega, and Hyoscyamus; with licorice, ammonium chloride, and cocain; 
with rhubarb, angelica, Inula, saffron, fennel, gentian, zedoary root, 
myrrh, white agaric, camphor, and aloes in Warburg's Tincture. It 
occurs in several lozenge formulas with licorice and sassafras oil; with 
colts foot, licorice, sugar, acacia, horehound, wild cherry, anise, tolu, and 
Capsicum; with licorice, tolu, and sassafras; with colts foot, peppermint 
oil, licorice, tolu, anise, and Capsicum, and in other combinations of the 
same substances. It occurs in liquid products combined with buchu, 
nitrous ether, juniper berries, and Uva Ursi; with senna, Collinsonia, 
Hydrastis, Bikukulla, copaiba, and potassium iodide, and it is used as 
one of the ingredients of inhalant combinations with such substances as 
tolu, iodin, camphor, carbolic acid, and glycerin. 

A number of other species of Piper yield fruits resembling cubeb such 
as P. clusii of West Africa; P. borbonense of Bourbon; P. sumatranum 
and P. pedicellosum of India. The fruits of Toddalia lanceolata (Rutacese), 
of Litsea citrata and L. cubea (Lauracese) have been sold and substituted 
for genuine cubeb. 

The constituents of genuine cubeb thus far definitely determined are 
a volatile oil amounting to 10-20 per cent and consisting chiefly of terpenes, 
sesquiterpenes and sesquiterpene hydrate called cubeb camphor; resinous 
matter; a bitter principle, cubebin; an acid called cubebic acid (sup- 
posed to be the cause of the characteristic red color produced when an 
ethereal extract of cubeb is treated with sulphuric acid); starch, and 
fixed oil. 

The stem-free fruit yields about 20-25 per cent of its weight to ether. 
If a small portion of the ether-free extract is treated with a drop of con- 
centrated sulphuric acid, 1 mil of ether added and rotated until the ether 
is evaporated, a crimson color is obtained. Adulterated samples give a 
red color with brown streaks intervening, while spurious products give 
a brown color and a mace odor. 



BOTANICAL DRUGS 421 

Cubebin 

Cubebin has the composition C20H20O6. It forms white crystals melt- 
ing 132°, (a)z>= —45.45 in chloroform, soluble in alcohol and ether. It 
contains two hydroxyl groups. When dissolved in glacial acetic acid 
and dehydrated with hydr iodic acid cubebinic ether results. This sub- 
stance melts 78°, (ol)d = +23.04° in chloroform, forms white silky needles, 
soluble in alcohol, benzol, acetic acid, and chloroform, and but slightly 
in water. It contains no hydroxyl nor carbinol groups and is not acted 
upon by bromin, permanganate, or hydrogen peroxide. Cubebinic ether 
yields a primary alcohol, cubebinol, when reduced with alcohol and so- 
dium. Cubebinol crystallizes in silky needles, melting 92°, (o)d= +34.81° 
in chloroform, yielding an acetyl derivative melting 71°, (o)d= +23.12° 
in chloroform and a benzoyl derivative melting 154-155°, (a) D = —21.68° 
in chloroform. 

Cubeb Oil 

Cubeb oil is a viscid, light-green or bluish-green oil; colorless only 
when the last portions of the distillate winch are blue, are not added; 
specific gravity .905 -.925, (a) D = -20 to -40°. The solubility in 90 per 
cent alcohol varies, some oils being soluble in an equal part of the alcohol, 
others requiring a greater quantity. Oils distilled from old fruit are 
heavier than the normal and can be recognized by their action on potas- 
sium or sodium. A piece of freshly cut metal immersed in such an oil 
loses its luster, whereas an oil distilled from the fresh berries does not 
attack metal. The oil has the characteristic cubeb odor and a warm 
camphor-like taste, which finally becomes grating. 

CANNABIS SATIVA. (CANNABIS INDICA) 

The drug consists of the flowering tops of the pistillate plants of Can- 
nabis sativa (Cannabinacese) , an annual herb indigenous to Central and 
Western Asia and cultivated in India, Greece, and other tropical and 
temperate countries. 

Cannabis is used in remedies for delirium tremens, certain forms of 
insanity, mania, excessive and painful cough, tuberculosis, migrain, itch- 
ing of eczema, neuralgia, and severe pain of different kinds, and corns. 
It is also extensively employed in veterinary practice. 

In pills or tablets it is combined with ergot; phosphorus and iron 
carbonate; with sumbul, Hyoscyamus and Valeriana; with arsenous acid 
and reduced iron; with Digitalis and reduced iron; with zinc phosphide 
and hyoscyamin; with phosphorus, strychnin, and damiana; with Hyos- 
cyamus, Ignatia, opium, belladonna, Conium, Stramonium, and aconite; 



422 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

with coca, Valeriana, strychnin, codein, arsenous acid, and ferrous car- 
bonate; with strychnin, aconitin, zinc phosphide, and sodium arsenate; 
with morphin, Capsicum, Hyoscyamus, nitroglycerin, and oil peppermint ; 
with quinin, Hyoscyamus, strychnin, acetanilid, and arsenous acid; with 
Hyoscyamus and the bromides of sodium, potassium, and ammonium. 

Liquid preparations will follow the general type of the above men- 
tioned combinations. The well-known " chlorodyne " type of remedies, 
popular for colic, cholera morbus, neuralgia, etc., contain Cannabis sativa, 
morphin, Capsicum, hydrogen cyanide, chloroform, and oil of pepper- 
mint. Anodyne mixtures contain Cannabis sativa, Hyoscyamus, chloral, 
and potassium bromide. 

Corn remedies consist of a mixture of this drug and salicylic acid with 
collodion or an ointment base. 

Cannabis contains from 15-20 per cent of a resin (called cannabin) 
consisting of a number of substances, one of which cannabinol, occurs as 
a red oily substance. Cannabinol appears to be the substance which 
gives the drug its peculiar active properties. It has the empirical formula 
C21H30O2, and is very unstable. It has been separated from the drug and 
the method employed may be followed in isolating it for the purpose of 
testing. The sample is extracted with low-boiling petroleum ether and 
after recovering the solvent the resin is distilled under .1 mm. pressure in 
Claisen flasks fitted with Thome's taps. The fractions passing over 
between 190-230° are united, dissolved in alcohol and subjected to a freez- 
ing temperature to remove paraffins. The alcoholic solution is distilled 
under diminished pressure in a current of hydrogen to remove the alcohol 
and the residue again fractionated, using the same procedure as above 
at a pressure o f 0.1 m m. U^annabinol distills at 230° at this pressure. It 
is readily altered on exposure to air and light and loses its physio- 
logical activity. This change, due to oxidation, occurs in alcoholic and 
ethereal liquids, and is responsible for the loss of activity of the galenical 
preparations. It contains an hydroxyl. It forms a trinitroderivative 
and by the further action of nitric acid a complex substance, C23H29N3O12, 
and ultimately butyric and oxalic acids. Solutions of cannabinol in 
glacial acetic acid have a characteristic marked dichroism, being green 
by transmitted and red by reflected fight. The addition of alkali hydrox- 
ides to an alcoholic solution produces a deep-red color which is discharged 
by the addition of an acid. 

A petroleum ether extract of Cannabis or a petroleum ether extract 
of an evaporated alcoholic extract of the drug, on evaporation to dryness 
and treatment with absolute alcohol which has been saturated with dry 
hydrochloric acid gas, yields a bright cherry-red color which will disappear 
on dilution with alcohol or water. The same color is developed by con- 
centrated sulphuric acid in acetone or acetic acid solutions of the extract. 



BOTANICAL DRUGS 423 

Cannabis sativa or its active principle are best detected by their peculiar 
action on dogs. Shortly after receiving a suitable dose the animal vomits 
and becomes excitable, later incoordination follows, the dog loses control 
of its legs and the muscles supporting the head, so that when standing 
the feet are usually spread apart to maintain balance. A third stage 
finally develops in which the dog sinks to the floor as if exhausted, and 
passes into a deep sleep. 

Preparations known to consist only of Cannabis may be administered 
directly by means of hard gelatin capsules, but where the drug is suspected 
in complex mixture the active principle should be extracted by means of 
petroleum ether, or if this is impracticable, with alcohol. The alcoholic 
extract may be administered directly, but if petroleum ether is used the 
solvent should be recovered and the residue tested. 

Corn remedies are best treated with ether and the solution poured into 
absolute alcohol, when most of the inert material will separate out and 
the clear liquid can be used for testing. The mixture itself will often 
yield its Cannabis to the alcohol without dissolving in ether. 

The animal's mouth is opened by forcing the thumb and index finger 
of the left hand between the jaws back of the teeth. The capsule is then 
placed on the back of the tongue with the right hand and the mouth quickly 
closed; while still holding the mouth shut, the animal can be made to 
swallow the capsule by slapping it on the throat. 

The quantitative estimation of Cannabis sativa is at best only a 
measure of comparative activity. Any data obtained from any kind of 
a galenical preparation mean little except as to the relative activity of 
the particular product with respect to Cannabis. The activity of a dozen 
samples of drug answering the description of the Pharmacopoeia may all 
come within an average and a dozen other samples of the same appear- 
ance fall far below them. A pill, a liquid mixture, or a solid extract may 
have a certain comparative potency measured in respect to a high grade 
sample of crude drug, but the figure obtained on the unknown cannot be 
used as a basis for stating the actual quantity of drug present. 

The method of assaying Cannabis has already been described. 

Within recent years the cultivation of the drug has been developed in 
the United States and the quality of the product is equal to any that was 
formerly imported. The plant is bisexual, the male and female flowers 
being produced on separate individuals, and the drug consists of the tops 
and unfertilized flowers of the female. The reason for this peculiar dis- 
crimination is somewhat obscure, for investigation has disclosed that 
the male tops which are culled out from the field, possess a physiological 
action of the same character with an equal degree of potency as the 
female portions. 

In the eighth revision of the Pharmacopoeia, one of the specifications 



424 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

of the official drug was that its source should be the East Indies, though 
as an actual fact most of the shipments came originally from Greece. It 
is healthful to note that the East Indian myth has been left out of the 
ninth revision, but the unfertilized female tops are still the only portions 
recognized as representing the drug. There is undoubtedly good reason 
for demanding that the female tops should be unfertilized, but the reason 
for exclusion of the equally active male tops is not apparent. 

There is still a lingering disposition in the trade to distinguish between 
so-called Cannabis Indica and Cannabis Americana, and an imported and 
often inferior article is quoted at a higher price than the native grown. 
Both products are one and the same, however, and there is no more reason 
for discriminating between them than there is for trying to draw a dis- 
tinction between methyl salicylate and oil of gaultheria or between wild 
and cultivated ginseng or between first- and second-year Digitalis. 

HOPS 

Hops extract and the glandular powder called Lupulin are used medi- 
cinally for their tonic, sedative, and anaphrodisiac properties. They 
will be encountered in many tonic mixtures combined with malt, hypo- 
phosphites, glycerophosphates, Nux Vomica, etc. ; and in various sedative 
formulas with Scutellaria, Cyprepedium, lactucarium, and bromides. They 
are also used in gonorrhea and other irritated conditions of the genito- 
urinary organs. Their virtues seem to be adaptable either for the produc- 
tion or relief of sexual excitement, for combinations of hops with phos- 
phorus, zinc, and strychnin are used as remedies for restoring sexual tone, 
and combinations with Scutellaria, bromides, and other sedative drugs 
are prescribed for producing the opposite effect. 

The hop plant, Humulus lupulus, is now placed in the family Can- 
nabinacese, and the male and female flowers are produced on separate 
plants. The male flowers are yellowish white and arranged in panicles, 
the female are pale green and disposed in solitary, peduncled aments. 
The part of the plant used is the fruit or strobile. 

Lupulin is formed on the surface of the scale and in the dried fruit, 
existing in the state of very small granules. It is obtained by rubbing 
or threshing and sifting the strobiles, of which it constitutes from T V to 
-g- by weight. It is a yellowish powder, with the characteristic hop flavor 
and under the microscope is seen to consist of globules filled with a yellow 
matter. It is inflammable and when moderately heated becomes some- 
what adhesive. Lupulin should contain not more than 40 per cent of 
matter insoluble in ether and yield not more than 12 per cent of ash. 

A vast amount of literature exists concerning the chemistry of hops, 
but much of it is vague and empirical and it has remained for Power, 



BOTANICAL DRUGS 425 

Tutin, and Rogerson 1 to clear up many of the disputed points and to 
give us the first authoritative insight into the chemistry of the drug. 

An alcoholic extract of hops on evaporation yields a volatile oil having 
a characteristic hop odor, extractive matter, and about 14-15 per cent 
of a dark-green oily resin. From the portion of the extract soluble in 
water there may be isolated small amounts of cholin and Z-asparagin, 
tannin, potassium nitrate, a sugar yielding c/-phenylglucosazone, melting 
208°, and dark-colored, intensely bitter amorphous material. A volatile 
base with a coniin-like odor is also present, but has not been 
'identified. 

From the resin the following compounds have been isolated : ceryl alco- 
hol; hentriacontane, C31H64; a phytosterol, C27H46O; a phytosterolin 
(phytosterol glucoside), C33H56O6; a mixture of volatile fatty acids con- 
sisting of formic, acetic, butyric, valeric, a hexenoic acid, C6H10O2, boil- 
ing 204-208° identified as /3-isopropylacrylic acid, and nonic acid; satu- 
rated and unsaturated non-volatile acids including palmitic, stearic, cero- 
tic, linolic, cluytinic, C21H42O2, melting 69°; and an acid, C20H40O2; an 
isomer of arachidic acid; and two new crystalline phenolic substances, 
humulol, C17H18O4, melting 196°, with a pale-fawn color and a bitter 
taste, and xanthohumulol, C13H14O3, melting 172°, orange-yellow in color 
and tasteless. 

Humulol is soluble in sodium carbonate, but not in ammonium car- 
bonate or hydroxide. The alkaline solution is j-ellow deepening on stand- 
ing or when warmed. It gives a pale-yellow solution with concentrated 
sulphuric acid. Its alcoholic solution is uncolorecl by ferric chloride. It 
is insoluble in water, petroleum ether, or benzol, sparingly in ether and 
chloroform, more so in glacial acetic acid, and readily in alcohol and pyridin. 
When boiled with potassium hydroxide, humulol is resolved into p- 
hydroxybenzaldehyde, melting 118°, and giving a dark-violet color with 
ferric chloride, a crystalline acid, C15H14O5, melting 210°, and complex 
viscous products. 

Xanthohumulol is not decomposed on heating with potassium hydrox- 
ide, but dissolves with an intense yellow color. Its alcoholic solution is 
not colored by ferric chloride. With sulphuric acid the color is at first 
deep orange, but this soon fades to a colorless solution. It is readily 
soluble in ether, ethyl acetate, and pyridia, moderately in alcohol, and 
sparingly in benzol and glacial acetic acid. 

The authors conclude that the bitterness of hops is not due to any 
single substance, such as the so-called " hop-bitter acid " or " lupulic acid," 
but it is attributed to a number of amorphous substances and humulol. 
Some of these bitter substances are soluble in water while others are in 
the resin. The differentiation of the resinous materials as a, 0, and 7 
1 Trans. Chem. Soc, 103, 1913, 1267, 



426 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

resins probably has little significance, and in our work at least does not 
call for further comment. 

The presence of hop extract in a medicinal mixture is usually apparent 
by the odor. An aqueous decoction of an evaporated alcoholic extract 
of the sample will contain the amorphous bitter substance, which is remov- 
able by ether, after acidification, and thus easily separated from strychnin. 

An ethereal solution of the resin, after first washing with ammonium 
carbonate, will yield humulol to sodium carbonate, and by subsequent 
shaking with potassium hydroxide the xanthohumulol is extracted. Both 
of these phenolic substances can be recovered by acidifying the alkaline 
solutions and shaking out with ether. 

The identification of a small quantity of potassium nitrate in the sample 
will furnish further evidence of the presence of hop extract. 

COCILLANA BARK 

This drug, which has become a very valuable remedj^ for bronchial 
troubles, was discovered by Dr. Rusby. The tree, Guarea rusbii (Meli- 
acese), is a native of Bolivia, and the thicker bark from the trunk and 
branches furnishes the drug. 

The bark has a peculiar and rather nauseating odor and nauseous 
taste, and this characteristic is imparted to the extract. If ipecac is 
absent in remedies recommended for deep-seated coughs, the presence 
of cocillana may be suspected. 

It contains a small quantity of an alkaloid, about 2.5 per cent of resin- 
ous matter, 2.5 per cent of fixed oil, and a white crystalline hydrocarbon- 
like body, melting at 80° C, sublimable, with a peculiar aromatic odor, 
soluble in ether, chloroform, acetic ether, and acetic acid. 

PHYTOLACCA DECANDRA. POKEWEED. 

The pokeweed is a familiar plant all over the eastern portion of the 
United States. It is a rapid grower, the stalks often attaining a height 
of nine feet with a spread of equal diameter. The dark-purple berries 
ripen in the autumn and both these and the root are gathered and used 
as drugs. 

As an alterative the drug appears in remedies for syphilis combined 
with Stillingia, Smilax Pseudo-China (Bamboo brier), Xanthoxylum, and 
Lappa; or with red clover blossoms, Berberis aquifolium, Cascara amagra, 
Stillingia, Lappa, and potassium iodide, sometimes with Iris versicolor; 
as an antirheumatic it occurs with colchicin, digitalin, guaiac, and potas- 
sium iodide; and with lithium salts, salicylates, cimicifuga, and colchicin. 
It is also found in remedies for catarrhal conditions of the mucous mem- 



BOTANICAL DRUGS 427 

brane, obesity, tumors, congestions of the uterus, liver, etc., and consti- 
pation, and it has emetic properties. 

The organic constituents of the root have never been fully investi- 
gated, but they are reported to include a saponin-like substance, an alka- 
loid, starch, sugar, formic and other acids. The inorganic constituents 
amount to over 13 per cent and consist principally of potassium and 
calcium, probably in the form of formate and oxalate respectively. 

The fruit of Phytolacca abyssinica is reported to be a tape-worm 
expellant. 

HYDRANGEA ARBORESCENS. (HYDRANGEACE^) 

The wild hydrangea or seven barks is an indigenous shrub of the 
eastern portion of the United States south of southern New York. The 
root has long been esteemed as a remedy for calculus complaints, and is 
often present in cystitis mixtures combined with boric or benzoic acid, 
potassium bicarbonate, buchu, triticum, corn-silk, Viburnum prunifolium, 
and atropin. It will be found in combination with hthium salts; and with 
Uva Ursi and matico in elixirs. 

An aqueous solution of the alcoholic extract of the drug fluoresces 
on adding alkali. The presence of a crystalline glucoside, a saponin-like 
body, a sugar, and resinous constituents have been reported. 

A peculiar characteristic of the shrub is the peeling off of the stem 
bark, which detaches in several successive thin layers of different colors, 
and which has given rise to the popular name " Seven Barks." 

KRAMERIA. RHATANY 

Several rhatanies have appeared in the market, and there are three 
well-recognized commercial species, Peruvian rhatany, the root of Kra- 
meria triandra (Krameriacese) (Leguminosse) growing in Peru and Bolivia; 
Savanilla rhatany, from K. ixina, and possibly other species, growing 
in Colombia, Brazil, and British Guiana; Para or Brazilian rhatany from 
K. argentea of Brazil. 

Krameria has been used in a multitude of ailments, but is nowhere 
common. It owes its chief value to its astringency, though it is likewise 
slightly tonic. It is employed internally in menorrhagia, passive hemor- 
rhages, chronic diarrhea, mucous discharges, leucorrhea; locally for piles, 
anal fissure, and prolapsus ani, and as a styptic in oral hemorrhage of 
surface bleeding. In pills it will be found combined with cubeb and 
ferrous sulphate; with bismuth salts, opium, and licorice; in capsules 
with copaiba and cubeb; and in pile ointments with sulphur, zinc oxide, 
resorcin, stramonium, tannic acid, and oil of cade. 

The Para rhatany closely resembles the Savanilla variety. The drug 
contains from 8-20 per cent of tannic acid or a tannin-like substance 



428 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

giving a dark-green color with ferric salts. Starch, sugar, and calcium 
oxalate are also present. 

Krameria lanceolate of the Southern United States furnishes the Texas 
krameria, and K. cistoides of Chile is the source of the Payta krameria. 
The root of Leea speciosa (Yitacese) has been used as a substitute drug. 

The tincture of Savanilla rhatany forms a clear solution with water, 
which gives, with alcoholic lead acetate, a purplish precipitate and a color- 
less nitrate. The tincture of Peruvian rhatany gives a cloudy mixture 
with water, and a reddish-brown precipitate with alcoholic lead acetate 
with a light-brown filtrate. 

HAMAMELIS VTRGINIANA. WITCH HAZEL 

Distilled extract of Hamamelis virginiana (HamameHdacese) is a house- 
hold remedy for inflammatory conditions, sprains and bruises. 

The distilled extract is prepared both from the leaves and the bark 
which are macerated with alcohol of from 6-10 per cent strength and then 
subjected to distillation. 

A concentrated extract of the drug, representing the resinous portion, 
is called Hamamelin. This is considered of value as a remedy for piles, 
and may occur in ointments intended for this trouble. The extract is 
sometimes used in pill mixtures recommended for disorders of the female 
genito-urinary tract, and may be combined with hydrastin, Hyoscyamus, 
opium, Senecio, tannin, thymol, Chamalerium luteum, salicylic acid, boric 
acid, alum, and eucalyptol. 

The distilled extract is combined with glycerin, boric acid, and mucil- 
age of Irish mosb in lotions and jellies for sunburn, freckles, and inflam- 
matory conditions of the skin. 

TRIFOLIUM PRATENSE. RED CLOVER 

Hed clover blossoms of T. pratense and T. incarnatum (Fabaceae) 
are employed medicinally in alterative mixtures for scrofula and second- 
ary syphilis, in whooping cough remedies, and for washing ulcers. In 
alterative preparations the drug is combined with others of similar repute 
such as Stillingia, Xanthoxylum, Lappa, Phytolacca, Iris versicolor, Ber- 
beris aquifohum, Cascara amagra, Smilax species, and potassium iodide. 

The flowering tops of T. pratense ordinarily furnish the drug known 
as red clover blossom. The blossom is well known and needs no de- 
scription. It is the red, purple, or meadow clover. 

Power and Salway x reported the following summary of a chemical 
investigation made on this drug. An essential oil distilled from the alco- 
holic extract contained furfur aldehyde. The water-soluble portion of the 
1 Chem. Soc. Trans., 1910, 97, 231. 



BOTANICAL DRUGS 429 

alcoholic extract contained considerable sugar, yielding d-phenylgluco- 
sazone; salicylic and p-cumaric acid; iso-rhamnetin; a number of new 
phenolic substances; pratol, Ci 5 H 8 2 (OH)(OCH3), melting 253° C; pra- 
tensol, Ci 7 H 9 2 (OH)J, melting 225°; a substance, Ci4Hi 2 6 , melting 214°; 
the following glucosides — trifolin, C22H 2 20ii-H 2 0, melting 260°, which 
yielded on hydrolysis a yellow coloring matter trifolitin, Ci6Hi O 6 , melt- 
ing 275°, and rhamnose, C6H12O5; isotrifolin , C22H22O11, melting 250°; 
and quercetin, melting 235°. 

The portion of the alcoholic extract insoluble in water was chiefly 
resinous material. The following substances were obtained from it: 
myricyl alcohol; heptacosane; hentriacontane; sitosterol, C27H46O/ melt- 
ing 135-136° (cOz>= -34.4° in chloroform; lnfohaiiol_C2iH3402(OH)2, 
melting 295°; a dihydric alcohol; a mixture of fatty acids, chiefly pal- 
mitic, stearic, and linolic, and a small amount of pratol. 

The tops of T. incarnatum, the crimson, carnation, French or Italian 
clover, are terminal, oblong or ovoid 1-2 J inches long; flowers sessile 
§-§ inch long, calyx hairy, corolla crimson, equaling or exceeding the 
subulata plumose calyx-lobes. 

Rogerson 1 examined the flowering tops of the plant and obtained a 
small quantity of an essential oil, and in the aqueous solution of the alco- 
holic extract there were present a sugar yielding tf-phenylglucosazone, 
benzoic, and salicylic acids, pratol, quercetin, and a new glucoside, h> 
carna trin, C 2 iH 2 oOi 2 3H 2 0, melting 242-245°. The portion of the 
alcoholic extract insoluble in water consisted of a green resin, amounting 
to 4 per cent of the dried tops, from which were isolated incarnat yJL 
alcohol^ C34H69OH, melting 72-74°; hentriacontane; a phytosterol, 
C27H46O, melting 135-136° (a) D =— 41.7° in chloroform; trifolianol, 
and a mixture of fatty acids. 

Pratol 

This phenol, together with other substances, is removed by ether from 
an aqueous decoction of the alcoholic extract of the drug. On evaporat- 
ing the ether and subsequently treating the residue with insufficient ether 
to bring it entirely into solution, the pratol is left undissolved. It crys- 
tallizes from alcohol in needles, having a talon-like shape with curved 
edges. It is moderately soluble in hot alcohol but only sparingly in water, 
ether, chloroform, and benzene. It dissolves readily in hot aqueous 
sodium carbonate and hydroxide, yielding pale-yellow solutions. When 
dissolved in acetic anhydride and a drop of sulphuric acid added, a yellow 
coloration is produced. With ferric chloride no appreciable change in 
color is produced. 

1 Chem. Soc. Trans., 1910, 97, 1004. 



430 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Power and Salway state that pratol is isomeric with several flavone 
derivatives such as the 2-methoxy and 3-methoxy-flavonol 

X) — C C 6 H 5 
CH 3 OC 6 H 3 < | 

XJ-OC-OH 

Its general behavior is similar to that of the above-mentioned substance, 
and it may represent one of the many hydroxymethoxy-flavones which 
are theoretically possible. 

Pratensol 

This phenolic substance goes into ether with comparative ease, and 
may be removed therefrom by alkali carbonates. It is readily soluble 
in alcohol and acetic acid, but only sparingly in water, chloroform, and 
benzene. Its alcoholic solution gives with ferric chloride a greenish- 
black coloration. 

Trifolin 

Trifolin gradually separates from the aqueous decoction of the alco- 
holic extract of the drug. On purification by repeated crystallization 
from aqueous pyridin it crystallizes in pale-yellow needles, which melt 
with decomposition at 260°. The water of crystallization is expelled at 
115°, but on exposure to the atmosphere this is reabsorbed. It is insoluble 
in cold water, chloroform, benzene, and ether. It is sparingly soluble 
in alcohol, but dissolves with ease in pyridin. With aqueous sodium 
carbonate and hydroxide it gives intensely yellow solutions. It dissolves 
in concentrated sulphuric acid to a yellow solution which rapidly develops 
a green fluorescense. In alcoholic solution it gives with ferric chloride 
a dark-brown color. 

When trifolin is hydrolyzed by sulphuric acid in alcoholic solution, 
it is resolved into trifolitin and rhamnose. 

C22H22O11 = C16H10O6+C6H12O5 

Trifolitin separates, after distilling off the alcohol, as a yellow precipi- 
tate, readily soluble in alcohol and glacial acetic acid, but only very spar- 
ingly soluble in ether, chloroform, and benzol. It dissolves in alkalies 
with an intense yellow color, and dyes mordanted cotton wool a bright 
yellow. It is precipitated from its alcoholic solution by lead acetate as 
an orange-yellow lead salt. Its alcoholic solution gives a dark-green 
color with ferric chloride. 

Isotrifolin 

This glucoside is soluble in water and may be removed therefrom by 
amyl alcohol. It yields the same hydrolytic product as trifolin, but it 



BOTANICAL DRUGS 431 

is evidently not identical with it. It melts at 250° and is much more 
soluble. Its general behavior is close to trifolin. It dissolves in alkalies 
with the formation of a deep-yellow solution, and gives with sulphuric 
acid a yellow color together with a green fluorescence. In alcoholic solu- 
tion it gives with ferric chloride a deep-brown color. 

Incarnatrin 

Incarnatrin, the glucoside of T. incarnatum, is soluble in water and 
is removed from the aqueous solution of the evaporated alcoholic extract 
of the drug by amyl alcohol, subsequent to the extraction of the phenols 
with ether. It hydrolyzes to quercetin and a sugar. 

C21H20O12+H2O = O5H10O7+C6H12O6 

The quercetin is soluble in ether, from which it may be removed by sodium 
carbonate. 

Incarnatrin is hydrolyzed by emulsin. It dissolves slowly in con- 
centrated sulphuric acid with a yellow color and a green fluorescence. 

XANTHOXYLUM 

The dried bark of Xanthoxylum americanum (Rutacea?) and of X. 
Clava-Herculis is official under the general name of Xanthoxylum. The 
berries are also used to a considerable extent. Both species of Prickly 
ash occur in the eastern portion of the United States, the former being 
the northern species or Toothache-tree and the latter the southern prickly 
ash, Hercules Club, or Pepper-wood. 

As a drug Xanthoxylum is used as an alterative, stimulant, and siala- 
gogue, and will be found in remedies for rheumatism, toothache, syphilitic 
and hepatic affections for increasing the secretions, and externally as a 
count er-irritant. 

Some of the liquid combinations which are recommended especially 
as alteratives or blood purifiers contain in addition to Xanthoxylimi, 
Bicuculla canadensis, Stillingia, Iris versicolor, and potassium iodide; 
or Trifolium pratense, Arctium lappa, Berberis aqiufohmn, Stillingia, 
Phytolacca, Cascara amagra, Bamboo-brier, and potassium iodide; liquid 
products in which the extract of the berries functionates contain also 
Stillingia, Bicuculla, Chimaphila, Iris, Sambucus, and coriander. Reme- 
dies in tablet form are of the same general type and in addition will be 
found tonic mixtures containing Cinchona alkaloids, Capsicum, and Cor- 
nus florida; ague pills with Cinchona alkaloids, Capsicum, and Gelsemium; 
and combinations with Cascara sagrada, Belladonna, Xux Vomica, Euony- 
mus, and Capsicum. The powdered bark is chewed as a remedy for tooth- 
ache and is also combined with Capsicum as a pack for pelvic pains. 




432 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

There are alkaloidal principles in this drug, but their identity is as 
yet uncertain. Formerly berberin was considered one of the constituents 
of the bark, and when chewed the saliva is colored yellow, but later 
investigation has cast some doubt on the identity of the alkaloid. Jowett 
and Pyman found canadin and gamma-homochelidonin in X. brachyacan- 
thum, but the chemistry of the Xanthoxylums needs further study. 

EUPHORBIA PILULIFERA 

Euphorbia pilulifera (EuphorbiaceaB), Queensland asthma herb, is an 
annual herbaceous plant growing in tropical countries and is reputed to 
be of value in the treatment of bronchitis, asthma, and other diseases of 
the respiratory organs. An extract of the entire plant is used in medi- 
cine and it is usually combined with iodides, bromides, Lobelia, and 
nitroglycerin, the combinations being dispensed in tablet and elixir form. 

Power and Browning x conducted an extensive chemical research on 
the drug and from the portion of the alcoholic extract which was soluble 
in water the following substances were isolated; gallic acid; quercetin, 
C15H10O7; a new phenolic substance; amorphous glucosidic material; a 
sugar yielding a phenylglucosazone, melting 218-220°, and a trace of 
alkaloid. 

The portion of the alcoholic extract insoluble in water consisted of 
soft, resinous material amounting to 3.2 per cent of the weight of the crude 
drug. This resin yielded triacontane, C30H62; ceryl alcohol; a new mono- 
hydric alcohol euphosterol, C25H39OH, melting 274-275°; a phytosterol, 
melting 132-133°; a phytosterolin (phytosterol glucoside); jambulol, 
Ci6H304(OH)5; melissic, palmitic, oleic, and linolic acids. 

About one-half of the resin is soluble in petroleum ether and after 
separating the solvent, extracting the undissolved portion with ether and 
separating the latter, the jambulol is obtainable by treatment with hot 
chloroform, from which it is partly deposited on cooling. 

Subsequent to this investigation it has been shown that jambulol is 
identical with ellagic acid. 

STILLINGIA 

Stillingia sylvatica (Euphorbiacese) is an herbaceous perennial found 
in dry sandy soil and in pine barrens from Maryland southward, and 
westward to Kansas and Texas. The root is esteemed for its alterative 
properties and is a popular component of spring tonics and blood puri- 
fiers. 

Stillingia will be found in elixirs, syrups, extracts, pills, and tablets 
combined with one or several of the following drugs : Bicuculla canadensis, 
Chimaphila, Iris versicolor, Sambucus, Xanthoxylum, Arctium lappa, 

1 Pharm. J. ; 1913. 



BOTANICAL DRUGS 433 

Phytolacca, Bamboo-brier, Trifolium pratense, coriander, and potassium 
iodide. 

Stillingia root contains a small quantity of volatile oil and an alkaloid. 

jKAMALA 

Kamala consists of the glands and hairs from the capsules of Mallotus 
PhiUipinensis syn. Rottlera tinctoria (Euphorbiacese) . The fruit is a 
roundish, three-valved, three-celled capsule of about the size of a cherry, 
marked externally with three furrows, and thickly covered with a red 
powder, which, when separated from the capsules, constitutes the official 
drug. 

It is used principally as a tape-worm expellant combined with aspidium 
in a medium of olive oil and dispensed in capsule form. The tincture is 
administered for tape worm, and the ointment for ring worm and parasitic 
skin diseases. 

Kamala is a light, finely granular, very mobile powder of a brownish- 
red, or madder color, with slight odor or taste but producing an acrid sen- 
sation in the mouth and a gritty feeling between the teeth. It is inflam- 
mable. It is insoluble in cold and very slightly in boiling water, largely 
soluble in ether, alcohol and alkalies. The chief constituent of kamala 
is a resin, the composition of which has not been reported. 

The ash of the pure drug should not run over 8 per cent, but in adulter- 
ated specimens it may reach as high as 50 per cent or more. Formerly 
much of the kamala imported was adulterated with sand and reddish 
earth, but this condition has been improved during recent years. 

EUONYMUS ATROPURPUREUS. WAHOO 

The root-bark of Euonymus atropurpureus (Celastracese) , known as 
burning bush or spindle tree, is employed to a considerable extent medi- 
cinally, and is recognized in the National Formulary and British Pharma- 
copoeia. The name " wahoo " is applied indiscriminately to E. atro- 
purpureus and E. americanus, the latter a low or trailing bush having 
crimson capsules to which the appellation " burning bush " is perhaps 
more applicable. Both species are used in medicine, but the former 
only is official. 

The extract is often combined with Podophyllum resin in remedies 
for the liver. It is precribed for intermittent fevers and dj^spepsia, and as 
a laxative, antiperiodic, and tonic. A crude resinous product or con- 
centration, and an alcoholic extract of the drug, are known under the 
name of " Euonymin," and the term is also applied to a number of sub- 
stances which at one time or another have been obtained from the bark, 



434 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

all of which, however, are of indefinite character. Some extracts with 
a greenish color are obtained from the tree bark, and these appear to be 
equally active physiologically. 

Euonymus extract is dispensed alone in pills, tablets, and elixirs, and 
in various combinations with Cascara sagrada, belladonna, Capsicum, 
Nux Vomica, and Xanthoxylum; with Taraxacum, Podophyllum, Apo- 
cynum, Eupatorium, Capsicum, and Chelone; with Iris, Podophyllum, 
and Sanguinaria; and with Podophyllum, ipecac, aloin, and calomel. 

Rogerson 1 made a systematic chemical examination of the root bark 
of E. atropurpureus. An alcoholic extract when distilled with a current 
of steam yielded a small quantity of a fragrant, yellow volatile oil. The 
portion of the extract soluble in water, contained a quantity of dulcitol, 
amounting to about 2 per cent of the weight of the drug; a new acid, 
C5H4O3, melting 121-122°, evidently furan-/3-carboxylie acid; a new 
^crystalline alcohol, C21H30O4, melting 248-250°, designated euonymol; a 
sugar which yielded a d-phenyl-glucosone, melting 208-209°, small amounts 
of tannin and coloring matter. 

The portion of the extract insoluble in water consisted of a dark-brown 
resin which amounted to 3.2 per cent of the weight of the drug. From this 
resin the following substances were isolated: euonysterol, C31H51O — OH, 
melting 137-138°, (a)/)-28.2°; ^homoeuonysterol, C 4 oH 69 0-OH, melting 
133-134°; atropurol, C 2 7H44(OH) 2 , melting 283-285°; citrullol, 
C22H3602(OH)2, a substance previously isolated from colocynth; and a 
mixture of fatty acids consisting of palmitic, cerotic, oleic, and linolic 
acids. 

Citrullol is probably a phytosterol glucoside and it is not unlikely 
that some of the other substances above mentioned may belong to the 
same class. 

Euonymol is bitter, soluble in alcohol and ether, from which it is not 
removed by acids or alkalies. If a crystal be dissolved in a small quantity 
of acetic anhydride and a few drops of concentrated sulphuric acid added, 
a pink color develops, changing to green with a bronze fluorescence and 
finally becoming yellow. When dissolved in sulphuric acid it gives a 
yellow solution with a greenish-yellow fluorescence. When boiled with 
acetic anhydride and the resulting product recrystallized from ether and 
ethyl acetate, the acetyl derivative melts 215°. 

Euonysterol resembles the phytosterols in its reaction with acetic 
anhydride and sulphuric acid, but with concentrated sulphuric acid alone 
a red color is produced. Its acetyl derivative melts 116-118°. 

Homoeuonysterol also gives a red color with sulphuric acid. Its 
acetyl derivative melts 128-130°. 

Atropurol gives no color reaction with sulphuric acid alone, but with 
1 Trans. Chem. Soc, 101, 1912, 1040. 



BOTANICAL DRUGS 435 

acetic anhydride resembles the phytosterols. Its acetyl derivative melts 
169-170°. 

Furan-/3-carboxylic acid is isomeric with pyro-meconic acid. It gives 
no color with ferric chloride. It is volatile with steam and sublimes 110°. 

Previous workers have reported the existence of a well defined gluco- 
side called euonymin, having a physiological action resembling that of 
the Digitalis glucosides, but Rogerson was unable to confirm this con- 
tention. 

SUMBUL 

Sumbul or Musk Root consists of the dried rhizome and roots of an 
umbelliferous plant which the U. S. Pharmacopoeia designates as Ferula 
sumbul. There is some doubt as to the identity of the botanical individual 
yielding the drug which is at present sold on the market. 

Sumbul is a nerve stimulant and is combined with Hyoscyamus, 
Valerian, and Cannabis; with ferrous sulphate, asafetida, and arsenous 
acid; with the valerianates of iron, zinc, and quinin; with iron, arsenous 
acid, and strychnin; and with Nux Vomica and Coca. 

Heyl and Hart 1 examined commercial musk root and found present 
a volatile oil amounting to 0.65-1.1 per cent, specific gravity .932 at 15°. 
This oil on standing deposited a few yellow crystals, melting at 113-114°, 
but not identified. No sulphur was found. 

An alcoholic solution of the drug yielded to water 1.7 per cent sucrose, 
1 per cent levulose, acetic acid, betain, and a glucoside of umbelliferone. 
The portion of the alcoholic extract insoluble in water was of resinous 
character. 

On treating the resin with petroleum ether, there was obtained a 
considerable proportion of a white acid resin, soluble in 1 per cent potas- 
sium hydroxide, and yielding upon hydrolysis vanillic acid and an oil 
resembling the volatile oil. The petroleum ether portion also yielded a 
phytosterol, melting 134-135°; an unsaponifiable substance, boiling 168- 
173°, at 12 mm., the analysis of which indicated the formula, C8H13O; 
and the following fatty acids from saponification of the glycerides, acetic, 
butyric, valerianic, tiglic, angelic, oleic, linoleic, cerotic, palmitic, and 
stearic. On subsequently treating the resin with ether, a phytosterolin, 
C33H56O6, melting 290° was obtained, also a trace of vanillin, resin esters 
yielding umbelliferone, and resin acids yielding vanillic acid and umbellif- 
erone on hydrolysis. Chloroform dissolved out a resinous glucoside 
which gave umbelliferone and glucose upon hydrolysis. 

An indication that sumbul is present in a medicinal preparation will 
be obtained in the regular scheme of analysis when the aqueous decoction 
of an alcoholic extract is made alkaline. On adding ammonia, for instance, 
1 J. Amer. Chem. Soc, 1916, 432. 



436 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

a yellowish-green flourescence is produced. This test is not specific as 
there are other drugs containing umbelliferone, and still others which 
produce blue or greenish fluorescences with alkalies. 

The odor of the drug differs markedly from that of asafetida and the 
volatile oil contains no sulphur. 

COTTON ROOT BARK 

Cotton root bark has obtained considerable reputation as an emmen- 
agogue and abortifacient, and is often present in female pills and in secret 
remedies advertised for restoring the menstrual periods. Some of the 
combinations containing the drug comprise ergot, aloes, savine, and fer- 
rous sulphate; Cimicifuga, aloes, and ferrous sulphate; ergot, Helleborus 
niger, aloes, savine, and ferrous sulphate. 

Pow T er and Browning 1 investigated the drug from a chemical stand- 
point. A concentrated alcoholic extract distilled with steam yielded a 
small quantity of a volatile oil which gave the furfurol color test, and 
deposited crystals of acetovanillone, melting 112-114°. The portion of 
the alcoholic solution soluble in water, and the insoluble resin contained 
a phenolic acid, probably 2-3 dihydroxybenzoic acid melting 196-199°; 
salicylic acid; a new phenolic substance, C9H10O3, melting 258-260°; a 
new yellow phenolic substance, melting 210-212°; betain; a fatty alcohol, 
C20H42O, melting 77.5-78.5°; a phytosterol; a small amount of an hydro- 
carbon, probably triacontane; ceryl alcohol; oleic and palmitic acids, 
and a sugar yielding d-phenylglucosazone. No tannins nor alkaloids were 
present. 

DAMIANA 

The drug damiana has been widely exploited in tonics and tonic bever- 
ages, as a remedy for restoring the sexual tone. In medicinal compounds 
it is usually combined with Nux Vomica or strychnin, phosphorus, zinc 
phosphide, cantharides, gold, and sodium chloride, and iron salts. Its 
presence should be suspected in any medicine used as an aphrodisiac. 

Tonic beverages which claim to contain damiana have been quite exten- 
sively marketed. These products usually bear striking pictorial devices 
of nude women and men in suggestive attitudes. As a rule the amount 
of damiana which is present in these mixtures is very small and often it 
is entirely lacking, and while sometimes the tonic may be fortified with 
strychnin or phosphorus, it usually consists of a mixture of water and 
alcohol, sweetened and flavored, and the picture is depended upon to 
stimulate the sexual activity. 

The leaves of more than one species of damiana occur in the trade, 
ipharm. J., 1914,93,420. 



BOTANICAL DRUGS 437 

but the true drug is ascribed to Turnera diffusa var. aphrodisiaca, which 
is described as follows: 

Leaves with reddish stems, yellowish flowers and globular capsules 
may be present. Leaves 25 mm. long, oblanceolate to obovate, margin 
serrate-dentate, color light green (older leaves somewhat coriaceous and 
pubescent) odor aromatic, taste somewhat aromatic and bitter. 

The chemistry of damiana has never been reported, but it contains 
a small quantity of a volatile oil which gives the drug and its extract a 
characteristic odor, a small quantity of a bitter substance and a greenish 
resin. 

In pills, tablets, and elixirs the resin is easily found by evaporating 
an alcoholic extract of the sample and washing with water. The odor 
of damiana will then be apparent and the greenish resin left undissolved. 

In order to detect the presence of damiana in tonic beverages a sample 
of 100-200 mils should be evaporated to drive off the alcohol at the same 
time noting any odor which is evolved and comparing it with that given 
off by a known extract of authentic damiana previously prepared by the 
analyst ; often a slight characteristic odor will be the only thing that will 
indicate that damiana was ever used in making up the mixture. The 
residue is then transferred to a separator, rendered slightly acid if neces- 
sary and shaken out with Prolius mixture. The solvent is filtered, evapo- 
rated to dryness, the residue treated with warm water and the water 
decanted. If there is any resin present, it will be left in the residue and 
it may be treated with alcohol, collected in a small area, and the solvent 
carefully evaporated to prevent spreading. Damiana resin is of a deep 
dull-green color with a characteristic odor and is the most marked con- 
stituent of the drug. 

ASCLEPIAS TUBEROSA. PLEURISY ROOT 

The root of Asclepias tuberosa (Asclepiadacese), butterfly weed, or 
orange milk weed is the official Pleurisy root or Asclepias. The plant is a 
very showy perennial and is common all over the East and in the South- 
west, through Texas and Arizona. It differs from the other species of 
milkweed in having no milky juice in its stem. 

Pleurisy root will be found in stomach tonics, and it is also used in 
affections of the lungs to promote expectoration, to relieve tight breathing 
and pain in the chest. It will be found combined with opium, camphor, 
and potassium bitartrate, and the powdered drug is one of the components 
of a popular remedy for the liquor habit, which includes also Taraxacum, 
ginger, Capsicum, Angelica and bayberry bark. 

The chemistry of the root A. tuberosa has never been definitely deter- 
mined, but it probably contains considerable starch, and a resin which is 



438 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

partially soluble in ether. The latter has been called asclepiadin, a gluco- 
side, but there is no evidence to show that it is an individual substance, and 
in view of our recent knowledge of these resinous bodies it is undoubtedly 
a mixture. 

Some of the other species of Asclepias have been used as medicines. 
A. verticillata is used in the South as a remedy for snake bites and the 
stings of venomous insects. A. syriaca is the common milkweed or silk- 
weed, and its root has been employed in asthma and scrofula. A. incar- 
nata, the flesh-colored or swamp milkweed is employed as an emetic and 
cathartic. 

The presence of milkweed roots in mixed liquid products can be detected 
only by the characteristic bits of vegetable tissue or of starch grains. The 
drug may occur in certain types of popular remedies mixed with rhubarb 
or other emodin-bearing drugs, buchu, juniper, • aromatic balsams, and 
sugars, and is recommended for alleviating abnormal conditions of the 
kidneys and stomach. 

ERIODICTYON. YERBA SANTA 

Eriodictyon calif ornicum syn. glutinosum (Hydrophyllacese), an ever- 
green shrub of California and Northern Mexio, is the source of the official 
drug Yerba Santa. The plant is also known as consumptive weed, tar 
weed, mountain balm, bears weed, and gum bark. It is employed for 
throat and bronchial affections as a tonic expectorant, and often occurs 
in preparations containing quiriin, for the purpose of obtunding the bitter- 
ness of that alkaloid. 

The drug contains a considerable amount of resin which is ordinarily 
insoluble in aqueous menstruum and syrups, and hence would be value- 
less for admixture with liquid quinin preparations unless prepared with 
a proportion of alkali sufficient to overcome the precipitation. The 
presence of an alkaline reaction therefore in quinin mixtures, and the pre- 
cipitation of resinous matter on adding acid, is a strong indication that 
Yerba Santa has been used. 

In medicines intended for expectorants it is combined with licorice, 
wild cherry, bromides, tar, Grindelia, salicylic acid, and senega, and it 
will be found in tablets, syrups, or glycerides. 

Power, Tutin, and Clewer 1 have examined the drug and the substances 
isolated therefrom. They determined that the leaves contain an essential 
oil, resins, amorphous products, glucose, the hydrocarbons triacontane, 
and pentatriacontane, formic, acetic, butyric, cerotic, and other acids, 
both in the free state and as glycerides, a small amount of a phytosterol, 

1 Proc. Am. Pharm. Ass., 1906, 54, 352; Trans. Chem. Soc, 1909, 81; Trans. Chem. 
Soc, 1910, 97, 2054. 



BOTANICAL DRUGS 439 

and five new crystalline substances of phenolic character ; / eriodicty ol, -" 
C15H12O6, melting 267°; ho moeriodic tyol, C16H14O6, melting 223°; cju^cse — ■» 
erid ol, C16H12O6, not melting up to 337°; xajitho^rioLol, C18H14O7, melting 
258°, and eriodonol, C19H18O7+H2O, melting 199°, and when anhydrous, 
melting 209 . No alkaloidal substance was present. 

The total amount of crude resinous material in the leaves amounts 
to 29-30 per cent, about 75 per cent of which is soluble in ether. The 
crude resin has an odor suggestive of tolu. 

The phenolic bodies are the characteristic ingredients of Eriodictyon, 
and are found both on the resinous portions and in the aqueous decoction 
of the evaporated alcoholic extract of the drug. When the evaporated 
alcoholic extract is treated with boiling water, the aqueous solution con- 
tains eriodictyol" with a suspension of homoeriodictyol, which appears as 
a yellow solid on cooling. Further quantities of the latter substance with 
some of the former and the three other homologues are subsequently found 
in the resin. 

The aqueous solution obtained as above mentioned, after filtering from 
the separated homoeriodictyol, is shaken with ether which dissolves the 
eriodictyol, and the latter may then be extracted from the ether by a 
saturated solution of sodium carbonate, previously washing the ether 
solution with ammonium carbonate to remove resinous matter. On 
acidulating the alkaline solution and shaking with ether, the phenolic 
body dissolves and on evaporating the solvent it will be left as a yellow 
varnish, yielding pure fawn-like crystals on recrystallizing from hot alco- 
hol, after shaking with animal charcoal. The alkaline solution must be 
at once acidulated as the solution rapidly turns brown when exposed to 
the air. 

Power and Clewer in their work fractionated the resin by repeated 
extractions with sodium carbonate, and thus obtained the several high- 
melting phenolic substances above mentioned. The resin was first 
extracted with petroleum ether to remove the acid and hydrocarbon con- 
stituents and the residue treated with ether. The etheral solution after 
washing with ammonium carbonate, was extracted with 34 successive 
portions of 5 per cent sodium carbonate. For each of the first 15 fractions, 
20 mils of the solution was employed, for each of the next 10, 50 mil por- 
tions, and for the remainder 100-mil quantities. The first and last frac- 
tions yielded only resinous matter, fractions 2-13 yielded xanthoeridol, 
4-26 eriodictyol, 15-26 chrysoeridol, and 27-33 eriodonol. Homoerio- 
dictyol separated as a sodium compound, which was collected on a filter, 
washed with ether and a little water and then recrystallized from water. 

The procedure adopted by these chemists for the separation of the con- 
stituents of Eriodictyon has been detailed here in order to point out to the 
analyst of an unknown mixture, a method for determining the presence 



440 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

of this drug. The systematic examination of a liquid or solid medicinal 
compound according to the qualitative scheme of analysis which is recom- 
mended for such mixtures, will furnish an aqueous solution and a residue 
of resinous character which can be adapted to the tests of Power and 
Clewer. 

Eriodictyol 

Tutin has determined that this substance is 2 : 4 : 6-trihydroxyphenyl 
3 : 4-dihydroxystyryl ketone 

_ 0I L 

HO/ ~")>CH : CH : Co/~ \oH 
HO OH 

It forms fawn-colored plates from glacial acetic acid, darkening and melt- 
ing to a red liquid at 267° C, moderately soluble in hot alcohol and acetic 
acid, very sparingly soluble in boiling water and insoluble or very sparingly 
so in the other organic solvents. It dissolves readily in alkali carbonates 
and hydroxides, the solutions rapidly absorbing oxygen and becoming 
deep brown. Ferric chloride gives a deep greenish-brown color rapidly 
changing to pure brown, when added to an alcoholic or aqueous solution. 
Its saturated aqueous solution does not reduce Fehling's solution, is not 
appreciably precipitated by normal lead acetate, but with basic lead 
acetate it affords a bulky yellow precipitate. Its acetyl derivative melts 
195-196°. On hydrolysis with acids it yields phloroglucinol. 

Homoeriodictyol 

(2:4: 6-trihydroxyphenyl-4-hydroxy-3-methoxystyryl ketone.) 

OH 

Ho/~ NcH : CH : Co/~ ~NoH 

CH3O ~~ OH 

Homoeriodictyol is the monomethyl ether of eriodictyol, and is readily 
obtained in a pure condition by dissolving in ether and shaking with sodium 
carbonate when a sodium derivative of homoeriodictyol separates, which 
may be recrystallized from water, and then decomposed by dissolving 
in hot water and adding dilute acetic acid. It crystallizes from 70 per 
cent acetic acid in lemon yellow plates, melting 223°. It is very sparingly 
soluble in water, but more readily in alcohol and acetic acid than erio- 
dictyol. It dissolves in alkalies with a bright yellow color. Its alcoholic 
solution gives an intense red-brown color with ferric chloride. Its aqueous 
solution is not precipitated by either of the lead acetates. No crystal- 
line acetyl or benzoyl derivatives have been prepared. It possesses a 



BOTANICAL DRUGS 441 

very slight sweet taste. On hydrolysis it yields feriilic (4-hydroxy-3- 
methoxy cinnamic acid) and phloroglucinol. 

This body appears to occur in considerably greater amount than any 
of the other phenolic compounds, Power and Tutin reporting the pres- 
ence of 3 per cent. It is isomeric with hesperitin, which is obtained by 
the hydrolysis of the glucoside hesperidin, a constituent of the peel of the 
orange, lemon, and other related fruits. Hesperitin crystallizes in color- 
less needles, melting 226°, soluble in alkalies to a faint-yellow solution, 
and possessing a sweet taste. It yields isoferulic (3-hydroxy-4-methoxy 
cinnamic acid) and phlorogulcinol on hydrolysis. 

Xanthoeridol, CisHnO^OH^ 

Xanthoeridol crystallizes from a mixture of ethyl acetate and alcohol 
in tufts of soft yellow, needles melting 258°. Its solutions in alkalies 
and concentrated sulphuric acid are yellow, and an alcoholic solution 
gives a dark-brown color with ferric chloride. Its acetyl derivative when 
recrystallized from acetic anhydride melts 175-176°. 

Chrysoeridol, C 1G Hg0 3 (OH)d 

Chrysoeridol is easily separated from eriodictyol, with which it is 
associated on account of its slight solubility in alcohol. It separates from 
boiling alcohol in golden-yellow leaflets which do not melt up to 337°. 
Its color reactions are similar to those of xanthoeridol. Its triacetyl- 
derivative when crystallized from acetic anhydride melts 211-212°. 

Eriodonol, Ci 9 Hi 4 3 (OH)4 

This substance crystallizes from slightly diluted alcohol in pale yellow 
needles containing one molecule of water melting 199°. When heated 
at 110° the water is expelled and the anhydrous body melts 209°. It 
is readily soluble in ethyl acetate, absolute ethyl, and methyl alcohols. 
When treated with concentrated sulphuric acid, the crystals become orange 
and dissolve to a yellow solution with a slight fluorescence. It gives a 
dark purplish-brown color with ferric chloride. Its solutions in alkalies 
are bright yellow. It yields iodoform when warmed with iodin and sodium 
carbonate, differing in this respect from the two substances previously 
described. It dyes linen mordanted with alumina or iron, bright yellow 
or dark brown respectively, and is thus similar to the tetramethyl ether 
of quercetin. It forms a tetracetyl derivative, melting 131°. 

PICHI 

Pichi is the dried leafy twigs of Fabiana imbricata (Solanaceae), a shrub 
with small scale-like leaves, indigenous to Chile. It contains a volatile 
oil, a bitter alkaloid, resin, and a substance resembling aesculin. 



442 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Pichi will be found in diuretic mixtures combined with corn-silk and 
triticum. 

An aqueous liquid obtained by washing an evaporated alcoholic extract 
of pichi shows a pink fluorescence when acidulated. The color turns 
blue on adding ammonia, the fluorescence persisting. 

The resinous portion of the drug contains a resene which is soluble 
in ether and may be sublimed. The resene obtained in this way gives a 
yellow color with concentrated sulphuric acid, becoming red on warming. 
When dissolved in carbolic acid, treated with zinc chloride and warmed, 
a yellow-brown color is obtained; on adding concentrated sulphuric acid, 
a rose-red color appears, soon changing to purple. 

COLLINSONIA CANADENSIS. STONEROOT 

Coilinsonia canadensis (Labiatse), horse or ox-balm, citronella or rich- 
weed, a perennial aromatic herb growing in moist woods in the eastern 
and central portions of this country, furnishes the drug known as stone- 
root. 

Stoneroot is diuretic, alterative, and tonic to mucous tissues, and is 
employed in chronic catarrhal affections of the stomach and genital organs. 
It will be found in elixirs combined with Chondrodendron tormentosum, 
buchu, and juniper berries, and its presence may be suspected in any pro- 
prietary remedy intended to alleviate chronic ailments of the kidneys. 
It is a popular remedy for that condition of the larynx known as " Minis- 
ters' Sore Throat." 

The flowing top of the green fresh herb has a limited use. The extract 
of this portion of the plant has a characteristic lemon-like odor and a 
peculiar aromatic taste. 

SCUTELLARIA LATERIFLORA. SCULLCAP 

The perennial herb, Scutellaria lateriflora (Labiatse) is the official 
Scullcap. There are several other species of Scutellaria and some of them 
no doubt are occasionally mixed and sold with the official drug. 

The drug was formerly held in great repute as a remedy for hydro- 
phobia, but its use for this disease has been largely abandoned, and it is 
now employed as a tonic, nervine, and antispasmodic, and will be found 
in remedies for chorea, convulsions, tremors, intermittent fevers, neuralgia, 
delirium tremens, and nervous affections generally. 

It is combined with Cypripedium, hops, and Lactuca canadensis in 
fluid extract scullcap compound; with Viburnum opulus and skunk cab- 
bage in female nerve remedies of the " Viburnum Compound "type; and 
in tablets with lupulin, ergot, atropin, and zinc bromide. 

There is no research recorded, dealing with the chemistry of S. lateri- 



BOTANICAL DRUGS 443 

flora. S. altissima, a foreign species, has been studied by Goldschmidt 
and Zerner, 1 and by Bargellini, 2 who worked on the composition and 
synthesis of scutellarin, a glucosidal body, which they extracted from the 
plant. Whether this glucoside exists in S. lateriflora has yet to be deter- 
mined. The researches of these chemists showed that scutellarin, 
C21H18O12, crj^stallized in yellow needles. When suspended in water, 
treated with concentrated sulphuric acid until it dissolved, and then 
poured into water, scutellarein, C15H10O6, was deposited and glucuronic 
acid remained in solution. When boiled with 25 per cent potassium 
hydroxide in a current of oxygen, para-hydroxyacetophenone resulted, and 
if hydrogen peroxide is added to the alkaline solution, para-hydroxyben- 
zoic acid is formed. 

Scutellarein on boiling with aqueous potassium hydroxide, gives para- 
hydroxyacetophenone and a substance resembling phloroglucinol in its 
color reaction with a pine splinter. Scutellarein gives the following colors 
on wool with the mordants mentioned; chromium, reddish brown; alumi- 
num brownish yellow; tin, lemon yellow; iron, olive green. 

In dilute alcohol glucuronic acid gives a green color when treated with 
alpha-naphthol and sulphuric acid; with more water the color changes 
through blue to violet and even to red. The green color is regenerated 
by concentrated sulphuric acid. The color reaction previously described 
for scutellarin is really a reaction for glucuronic acid. 

LEPTANDRA 

Leptandra or Culver's root is the rhizome and roots of Veronica vir- 
ginica (Scrophulariacese), a plant indigenous to North America. The 
drug has quite an extended medicinal use, and the crude resinous material 
obtained therefrom is one of the products to which the name " leptandrin" 
has been assigned. The term has also been applied to a glucosidal sub- 
stance reported as occurring in the root, but the existence of such a chemical 
individual is doubtful. Leptandra is also known as Bowman's root, tall 
speedwell, and tall veronica. 

The drug or its resinous constituents enter into a number of cathartic 
remedies and liver regulators, and usually will be found combined with 
Podophyllum resin. The cathartic pills and tablets consist of combi- 
nations of Leptandra with aloin, jalap, Podophyllum, gamboge, gentian, 
Capsicum, Hyoscj^amus, colocynth, and oil of peppermint. The liver 
combinations are of similar composition, but without Hyoscyamus and 
with the addition of calomel, Veratrum viride, and croton oil. Some 
special formulas contain juglans and Sanguinaria; Euonymus, creosote, 
chirata, and Iris versicolor; Leptandra is one of the constituents of the 
1 Monatsch., 31, 439. 2 Gazz. chim. ital., 45, I, 69. 



444 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

U. S. P. vegetable cathartic pills. It will be found in elixirs with Cascara 
sagrada, senna, juglans, and Rochelle salt, and in fluid extract mandrake 
compound with Podophyllum, senna, and jalap. 

Power and Rogerson 1 found that the root contained 6-7 per cent of 
a dark-brown resin, soluble in alcohol, from which they isolated a phytos- 
terol called verosterol, C27H46O, melting 135-136°, (a) D — 33.0°, a mix- 
ture of fatty acids (oleic, stearic, palmitic, and linolic), p-methoxycin- 
namic and 3 : 4-dimethoxycinnamic acids. The latter substance was also 
present in considerably larger quantity in an aqueous solution of the alco- 
holic extract of the drug, together with mannitol, a sugar yielding d-phenyl- 
glucosazone, melting 209-211°, tannin, coloring matter, and an intensely 
bitter amorphous substance. 

No glucosides were found, and the absence of saponin was established. 
The fact that an aqueous solution of 3 : 4-dimethoxycinnamic acid froths 
strongly on agitation, has doubtless led to the recorded statements of the 
presence of saponin in leptandra. 

The identification of Veronica virginica in medicinal mixtures by 
chemical means is not easy of accomplishment. The isolation of 3 : 4- 
dimethoxycinnamic acid would point strongly to the presence of the drug, 
but if " leptandrin," or the resinous portion were used alone, this acid 
would occur in minute quantity only, and probably would escape detec- 
tion. The isolation of verastrol from a mixture containing in all prob- 
ability other phytosterols, would be practically impossible. By centri- 
fuging a portion of the diluted alcoholic extract of the sample, any vege- 
table tissue present would be concentrated and by careful microscopic 
examination the characteristic feature of the drug might be detected. 

VERONICA OFFICINALIS 

The leaves and flowering tops of Veronica officinalis (Scrophulariaceae) 
the common speedwell or Paul's betony, are used in the form of an infusion 
for asthmatic troubles, coughs, and catarrh of the bladder. 

MITCHELLA REPENS. SQUAWVINE AND OTHER "SQUAW" DRUGS 

The original discovery of the efficacy of many drugs is often ascribed 
to the Indians, and this fact is featured in the literature of certain classes 
of proprietary remedies especially of the female regulator, spring tonic, 
and herbal compound type. For this reason there are several different 
drug plants to which the significant name of "Squaw " is attached, such 
as Squawvine, Squaw-weed, Squaw-root, etc. 

While there are probably several plants to which the name Squaw- 
vine is applied, the drug to which it belongs is Mitchella repens (Rubiacese), 
1 Trans. Chem. Soc, 1910, 97, 1944. 



BOTANICAL DRUGS 445 

the well-known partridge berry, a procumbent evergreen vine of our 
eastern woods. The entire aerial portion of the plant furnishes the drug. 

Mitchella repens is employed in dropsy, suppression of urine, diarrhea, 
and especially in deranged uterine conditions. Its presence may be sus- 
pected in any preparation, elixir, tablet, or ground mixed herb, called a 
female regulator, mother cordial, viburnum compound or squaw-weed 
compound. It is usually combined with Viburnum opulus (Cramp bark), 
Chamaelirium luteum (Helonias), Caulophyllum, Aletris farinosa (Star- 
grass) and Viburnum prunifolium (Black Haw). 

A survey of our North American botanical drugs shows the following 
list of common names suggestive of Indian origin: 

Squawhish. Viburnum opulus. 

Squaw flower. Trillium erectum (Wake-robin, birthroot). 

Squawmint. Hedeoma pulegioides (Pennyroyal). 

Squawroot. Applied to Caulophyllum thalictroides and Cimicifuga 
racemosa. (Blue and black cohoshes). 

Squaw-weed. Eupatorium ageratoides and several species of Senecio. 

Viburnum and the cohoshes have been given separate consideration. 

Senecio aureus (Composite), the Life-root or Swamp Squaw-weed, is 
the species of Senecio of importance medicinally. S. Robbinsii is called 
Robbins Squaw-weed; S. discoideus, Northern Squaw-weed; S. obovatus, 
Round leaf Squaw-weed; and S. Crawfordii, Crawford's Squaw-weed. 
S. Aureus is familiar to all in the early spring and summer as the golden 
ragwort, and is one of the earliest of the Composite to bloom. It is another 
of the numerous drugs which is supposed to have a special influence on 
the female reproductive organs and will be found in remedies for sup- 
pressed menstruation and other abnormal conditions of the uterine 
system. 

The herb and root furnish the drug. The flower resembles the 
arnica in some respects and the genus is closely related to the Arnicae. 

This plant has been reported as containing alkaloidal constituents, 
but its chemistry has never been carefully investigated. 

THE VIBURNUMS 

Several species of Viburnum (Caprjfoliaceae) have furnished drugs 
reputed of value in the treatment of asthmatic conditions, and for their 
uterine tonic and sedative effects. For a considerable period the identi- 
ties of the products sold on the market for true Viburnum, were in a 
confused state, and hence the descriptions credited to these drugs in the 
past must in some instances, be taken with reservation. 

There appear to be three species of Viburnum recognized as furnish- 
ing medicinal drugs. The cramp-bark is the bark of the indigenous shrub 



446 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

V. opulus, which grows from New Jersey, Michigan, and Oregon north- 
ward. The drug known as V. prunifolium is the bark of the root of the 
black haw, and the bark of the root of V. lentago, the former occuring 
from Connecticut to Georgia west to Michigan, Kansas and Texas, and 
the latter having a range from Hudson Bay to Manitoba to New Jersey 
and along the AJleghenies to Georgia, westward to Indiana, Kansas, and 
Colorado. V. lentago is the sweet viburnum, sheep- or nanny-berry, 
V. prumfolium, the stag-bush or slow berry, and V. opulus, the highbush 
cranberry. 

For a number of years and until quite recently the drug sold as cramp 
bark was not derived from V. opulus at all, but from the mountain maple, 
Acer spicatum. The drug described in the seventh and eighth revisions 
of the U. S. P. as V. opulus applies to Acer spicatum. The National 
Formulary, fourth edition (1916), correctly describes V. opulus. 

The reason for the indiscriminate gathering of the barks of the high- 
bush cranberry and mountain maple, is apparent to one familiar with the 
growing plants. Mountain maple assumes the appearance of a shrub 
at one stage of its growth, and the structure of its leaves differs from the 
usual forms of the maples, and in the eyes of the ordinary drug collector 
might readily be mistaken for Viburnum. One may often see the moun- 
tain maple growing side by side with Viburnum, and this condition appar- 
ently obtains throughout the range of both species. 

V. opulus is a component of many of the mixtures recommended in 
female complaints of the uterine tract, and is combined with Chamselir- 
ium, Caulophyllum, Mitchella, Aletris, Scutellaria, skunk cabbage, and 
V. prunifolium. 

V. prumfolium is combined with the above-mentioned drugs and in 
other combinations with Hydrastis and Jamaica dogwood (Piscidia,) with 
Hydrastis, Jamaica dogwood, Cimicifuga, Cascara sagrada, Hyoscyamus, 
Cannabis sativa, and Potassium bromide ; with boric acid, potassium bicar- 
bonate, buchu, Triticum, corn silk, Hydrangea, and atropin; with celery, 
coca, and kola. 

These combinations may be found in liquid, tablet, and capsule form. 

Viehoever, Ewing, and Clevenger * report the results of a research 
made with a series of commercial specimens of cramp bark and black haw 
collected in 1915, and examined as to their identity. Of the fifty samples 
of cramp bark examined, forty-eight were derived from Acer spicatum. 
The specimens of the black haw were true to name. In 1916 they examined 
samples of Viburnum preparations in general on the market and found 
that those of V. prumfolium were true to label, while nearly all of those 
supposed to be made from V. opulus contained no Viburnum at all, but 
gave positive tests for maple. 

1 J. Am. Pharm. Ass., 1918, (7) 944. 



BOTANICAL DRUGS 447 

There is no difficulty in distinguishing between the Viburnum and Acer 
barks, both microscopically and chemically. The tannins of the former 
give a green color or precipitate with freshly prepared iron salts, whereas 
the tannin of the latter gives a blue precipitate or color. 

When worldng with the crude drug, a cross-section or a small quantity 
of the powder is treated with a drop of freshly prepared ferrous sulphate 
(1-1000), and the characteristic colors develop in a few minutes. 

Another distinguishing test for maple bark is the red lignin reaction 
obtained when a drop of phloroglucin-hydrochloric acid (phloroglucin 
0.1 gram, alcohol, and concentrated hydrochloric acid 10 mils each) is 
applied to the inner side of the bark. Any wood fragments attached 
to the sample must be removed. The test is therefore applicable only 
in the case of the whole drug and not to ground samples. Viburnum barks 
yield but a faint reaction if any. When the above described reaction is 
carried out on Viburnum specimens, the odor of valerianic acid will 
develop. Acer barks do not yield this acid. 

To distinguish between maple and Viburnum tannins in pharmaceu- 
tical preparations containing alcohol, about 10 mils are diluted with three 
volumes of water and shaken out with 15 mils of ether. The ethereal 
layer is filtered and shaken in a test-tube with an equal volume of water 
containing two drops of freshly prepared saturated ferrous sulphate solu- 
tion. A green color in the lower layer indicates a Viburnum species, a 
blue color indicates a maple. 

A confirmatory test for the Viburnum species should be made by 
separating and identifying valerianic acid. If the sample is a fluid extract 
10 mils should be made alkaline with sodium hydroxide and boiled to 
expel the alcohol; if a mixed pharmaceutical is under examination, a larger 
quantity should be neutralized with sodium bicarbonate and evaporated 
to expel the alcohol. The alcohol free mixture is then acidified with sul- 
phuric acid, distilled with steam, and the presence of valerianic sought 
in the distillate. The acid may be separated from the distillate, by satu- 
rating with salt, shaking out with ether, transferring the ethereal solution 
and removing the solvent over the steam-bath. Viehoever and his 
coworkers identified valerianic acid by its boiling-point and by the char- 
acteristic microchemical forms of the copper, zinc, and mercury salts. 
The zinc compound prepared with zinc nitrate was the easiest to obtain. 

VALERIANA OFFICINALIS 

The rhizome and root of Valeriana officinalis (Valerianacese), the com- 
mon valerian, is used as a stimulant to the nervous system, and is a com- 
ponent of medicines used in hysteria, hypochondria, restlessness, and other 
nervous disorders. Valerian is combined with Hyoscyamus and camphor; 



448 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

with phosphorus and zinc salts; with Hyoscyamus, musk root (Sumbul), 
and Cannabis sativa; with coca, codein, Cannabis sativa, strychnin, 
arsenous acid, and ferrous carbonate; with Sumbul and asafetida; with 
Sumbul, asafetida, ferrous sulphate, and arsenous acid, etc. These seda- 
tive mixtures are usually dispensed in the form of pills and tablets, and 
are often sold at a high price with great claims as to their virtue in 
restoring normal sexual functions or for controlling abnormal condi- 
tions. The valerianates prepared from valerianic acid are often present 
in sedative mixtures, and these products as well as the description of 
valerianic acid have been discussed in the section of Pure Organic Bodies. 

The characteristic constituent of the valerian root is the oil which 
amounts to about 1 per cent, and which contains, among other constitu- 
ents, the valerianate of borneol. This ester gradually hydrolyzes, and 
hence the root and the extract have the odor of valerianic acid. The 
root of Valeriana mexicana yields an oil containing free valerianic acid, 
and Japanese valerian, which is probably a variety of V. officinalis, yields 
an oil which closely resembles the oil of the official drug, but which con- 
tains the acetate of an alcohol having the composition, C14H24O2, and 
termed kersyl alcohol. The latter substance crystallizes in large well- 
formed crystals, melting 85°. It is odorless, insoluble in water, readily 
soluble in organic solvents, boils 155-156° under 11 mm. pressure, and is 
laevogyrate. 

The odor of valerianic acid is apparent in examining other drugs and 
their extracts, notably the Viburnum, Angelica, Sambucus species, etc., 
hence it is necessary to use caution in diagnosing the presence of V. offici- 
nalis. 

Oil of valerian is a yellowish-green to brownish-yellow liquid, slightly 
acid, with a penetrating and characteristic and not unpleasant odor. Old 
oil is dark brown and viscid, with a strongly acid reaction due to the 
presence of free valerianic, formic, acetic, and butyric acids, often with 
considerable separated borneol, and having a disagreeable odor. The 
normal gravity is between .93-96, (a) D =— 8 to —13°, acid number 
20-50, ester number 80-100, and saponification number 100-150. 

BRYONY ROOT 

The drug known as bryony root is yielded by the plants Bryonia alba 
and B. dioica (Cucurbitacese) . Both of these plants are natives of Europe, 
but the latter is the species commonly found in England, and is fre- 
quently designated English bryony. The roots of both species are consid- 
ered by some authorities as possessing the same properties, and they 
appear to be collected and sold as bryony without regard to their botanical 
individuality. The roots of B. americana and B. africana are respec- 
tively used in the West Indies and Africa in cases of dropsy. 



BOTANICAL DRUGS 449 

Bryony root is an hydrogogue cathartic, and is chiefly employed in 
dropsy. It is also prescribed to a limited extent in chronic intermittent 
fever, enlargement of the spleen, chronic bronchitis, and catarrhal whoop- 
ing cough. It is usually dispensed in the form of tablet triturates and 
coated tablets. Bronchitis mixtures contain in addition to bryony, aco- 
nite, belladonna, tartar emetic, and potassium bichromate; fever com- 
binations include aconite and belladonna; and cold and fever mixtures 
contain aconite, Eupatorium perfoliatum, Gelsemium, and camphor, 
monobromate; tonsillitis compounds consist of aconite, belladona, and 
mercuric iodide, often with the addition of morphin and salicylates. 
For dropsical conditions the fluid extract or a tablet of the tincture are 
employed. 

Power and Moore * examined B. dioica chemically. An enzyme was 
found which hydrolyzed a glucosidic constituent of the root, and also 
acted on amygdalin and salicin. An alcoholic extract of the root yielded 
2 per cent of a resin and a water soluble portion which contained a colorless, 
crystalline, neutral substance, C20H30O5, melting 220-222°, slightly soluble 
in ether and when purified, almost insoluble in ether, but dissolving readily 
in alcohol. The water-soluble portion also yielded a glucoside, an amor- 
phous alkaloid and a sugar which formed a d-phenylglucosone, melting 
208-210°. The glucoside was soluble in amyl alcohol and ethyl acetate, 
bitter, precipitated from aqueous solution by tannin, and giving no color 
with ferric chloride. On hydrolysis with dilute sulphuric acid, it gave 
a brown resin and a sugar whose c/-phenylglucosone melted 208-210°. 
The alkaloid was intensely bitter, soluble in water and alcohol, but spar- 
ingly in ether and chloroform, and was precipitated by the usual alkaloidal 
reagents and tannin. Ammonia was evolved on heating with alkali 
hydroxide, and hydrochloric acid decomposed it with the formation of 
ammonium salt. 

The resin was dark brown, viscous, and completely soluble in ether. 
From it were isolated a phytosterol, C27H46O, melting 137° and optically 
inactive; bryonol, melting 210-212°, and a mixture of oleic, linolic, pal- 
mitic, and stearic acids. Bryonol belongs to the group of substances which 
Power and Salway have since concluded are phytosterol glucosides. Its 
solution in chloroform gave with acetic anhydride a series of color reac- 
tions similar to those produced by ipurganol, a purplish pink, changing to 
blue, green, and brown, and it dissolved in concentrated sulphuric acid 
with a yellow color, the solution showing a green fluorescence. It is closely 
allied to cucurbitol, a substance isolated from the resin of watermelon seed. 

The substance obtained from bryony root b} r precipitation with tannin, 
and designated " bryonin " by previous investigators, is evidently a com- 
plex mixture. 

1 Trans. Chem. Soc, 1911, 99, 937. 



450 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

PUMPKIN SEED 

The seeds of the common pumpkin, Cucurbita pepo (Cucurbitaceas), 
have attained considerable reputation for their taenicidal properties. The 
fluid extract is used for expelling tape-worm and in combination with 
Cascara, senna, Rochelle salt, Chenopodium, and sodium bicarbonate it 
is prescribed as a children's remedy. 

Power and Salway 1 determined that the seeds contained about 34-35 
per cent of a fixed oil removable by petroleum ether, consisting of the 
glycerides of linolic, oleic, palmitic, and stearic acids; a resin amounting 
to about 0.5 per cent; a small amount of salicylic acid; soluble proteins, 
sugar, and starch. Neither the oil nor the resin was found to effect the 
complete removal of tape-worm which was administered under the usual 
conditions of fasting and followed by a dose of castor oil. 

TARAXACUM 

The root of the well-known dandelion, Taraxacum officinale syn. T. 
taraxacum (Cichoriacese) , is a popular tonic and alterative. It is chiefly 
employed in derangements of the liver, in dyspepsia, in cutaneous erup- 
tion due to a disordered liver, and of late has been prescribed as an 
adjunct to the treatment of cancer. 

It is combined with senna; with Podophyllum and Conium; and with 
Sarsaparilla; with licorice and wild cherry; with licorice, gentian, verba 
santa, and Eucalyptus, etc., in liquid extracts and elixirs. In pills and 
tablets extract of Taraxacum is combined with quinin, arsenous acid, 
and iron; with podophyllum resin, Capsicum, Euonymus, Apocynum 
and balmony; with Nux Vomica, coiocynth comp., quinin, oxgall, and 
pancreatin and other similar combinations. 

Powered Taraxacum occurs mixed with Asclepias tuberosa, Ginger, 
Capsicum, Angelica, and Bayberry bark in a mixture designed as a secret 
remedy for intoxication and the drink habit. 

The plant grows all over the United States, but the drug is chiefly 
imported from Europe. 

Dandelion root contains considerable inulin and a laevorotatory sugar 
which appears to be mostly lsevulose. Power and Browning 2 found that 
an alcoholic extract of the drug yielded a resin and certain water-soluble 
substances, including/ p-hydroxy-phenylacetic acid, melting 144-146°; 3j_4__ 
dihydroxycinnamic acid, and cholin, C5H15NO2. The resin amounted 
tcTT.8 per cent of the weight of the dried root and yielded a monohydric 
alcohol, taraxasterol, C29H47OH, melting 221-222°, (gO.d+96.3 ; a mono- 
hydroalcohol homotaraxasterol, C25H39OH, melting 163-164°, (a)z>+25.3°; 

1 Journal Amer. Chem. Soc, 1910, 32, 346. 

2 Trans. Chem. Soc, 101, 1912, 2411. 



BOTANICAL DRUGS 451 

cluytianol, C29H460(OH)4 melting 297° (a phytosterolglucoside) ; palmitic, 
cerotic ancf melissic acids, together with a mixture of unsaturated acids, 
consisting chiefly of oleic and linolic, with apparently a little linolenic 
acid. 

An extract of Taraxacum root when extracted with Prolius mixture 
yields a trace of material giving a precipitate with Mayer's reagent. 

The alkaloid cholin probably furnishes the best indication of the pres- 
ence of the drug in medicinal mixtures. If an alcoholic extract is evapo- 
rated and treated with water, the cholin will go into the aqueous liquid. 
After precipitating with basic lead acetate, filtering, and removing the 
excess of lead with hydrogen sulphide, the filtrate on evaporation may be 
concentrated to a thick syrup, extracted with alcohol, filtered, the alcoholic 
solution concentrated and the treatment with alcohol repeated until no 
insoluble material remains. The alcoholic solution is then treated with 
a saturated solution of mercuric chloride in alcohol and allowed to stand 
several days. The precipitated cholin compound is then filtered, washed 
with alcohol, and dissolved as completely as possible in water, from which 
the mercury is precipitated with hydrogen sulphide. The filtered liquid, 
is neutralized with sodium carbonate, slightly acidified with hydrochloric 
acid, and evaporated to dryness in a vacuum desiccator. The dry residue 
is treated with absolute alcohol, filtered, evaporated, and the treatment 
with absolute alcohol continued until the inorganic salt is eliminated. 
The final product will be deliquescent and its aqueous solution gives a 
yellow precipitate with gold chloride. Its solution in absolute alcohol 
will give a precipitate with platinic chloride, which if dissolved in a 
little water will finally deposit in the form of reddish-brown plates, melt- 
ing with decomposition at 250-254°. 

It is probable that cholin is the substance to which the name " tar- 
axacin " was given by investigators who have, at one time and another, 
attempted to determine the constituents of Taraxacum. 

BURDOCK. ARCTIUM LAPPA 

Burdock root is a popular alterative. Its extract is employed in 
remedies intended for gout, rheumatism, leprosy, and similar diseases. 
It usually occurs in admixture with other drugs, especially Stillingia, 
Phytolacca, Xanthoxylum, red clover, and Iris. Mixtures of the Succus 
Alterans or Alterative compound type consist of bamboo-brier root, bur- 
dock, Xanthoxylum, Stillingia, and Phytolacca; those of the Trifolium 
compound order contain red clover, burdock, Berberis aquifolium, Xan- 
thoxylum, Stillingia, Phytolacca, Cascara amagra, and potassium iodide. 
These preparations are offered in the form of extracts, syrups, pills, and 
tablets. Sassafras is often present in syrups of burdock root. 



452 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The seed is used as a tonic and alterative and has been used success- 
fully in skin diseases, such as psoriasis. The fresh leaves have also a 
limited use. 

The roots of other species of Arctium are also uaed and are recognized 
in the U. S. Pharmacopoeia. It is directed that the drug be collected 
from plants of the first year's growth. The flowers are not produced 
until the second year. 

Very little work has been done on burdock root, but it apparently 
contains a sugar, inulin, and a fixed oil. 

GRINDELIA SPECIES. GUM PLANT OR TAR-WEED 

There are some thirty species of Grindelia (Composite) native of 
western North America, Peru, and Chile. About seventeen species occur 
in the western and southwestern parts of North America, G. squarrosa 
and G. lanceolata extending their range also east of the Mississippi. 

G. squarrosa occurs over a wide area, being found in dry soil in Illinois 
and Minnesota to Manitoba, Missouri, Texas, Arizona, and Mexico, and 
adventive in southern New Jersey, Pennsylvania, and New York. 

The plants furnishing the drug are commonly designated as the above 
and G. robusta, but it is probable that the botanical identities of the 
commercial products have been confused with other species. 

G. robusta is a somewhat rare plant and according to Perredes * occurs 
much too sparingly to be a factor of any importance in the consideration 
of the drug on the market. G. squarrosa appears to occur to a limited 
extent in Calif ornia, from which State a large part of the commercial drug 
is obtained. 

G. camporum occurs abundantly in the inner coast ranges, in the foot- 
hills of the Sierra Nevada, and is almost the only plant found on the plains 
in certain regions of the Sacramento Valley. G. cuneifolia is the next 
most abundant species in California; but G. camporum is the common 
" gum plant " of California. 

It is stated that when collectors are asked to furnish separately 
" Grindelia squarrosa " and " Grindelia robusta," the plant growing in 
the marshes (G. cuneifolia and its variety paludosa) is supplied for the 
latter, while G. camporum, the plant of the dry hills and plains is sup- 
plied for the former. 

The drug commonly occurring on the market is now probably largely 
G. camporum. 

Grindelia is used in the treatment of asthma, bronchial troubles, 
pertussis, catarrh of the bladder, and other diseases of the mucous mem- 
brane of the genito-urinary organs. Locally its tincture or fluid extract 
1 Proc. A. Pha. A., 1906, 54, 370. 



BOTANICAL DRUGS 453 

has proven of value in ivy poisoning. Fluid extract Grindelia compound 
contains senna and rhubarb. Bronchial mixtures will contain Grindelia, 
Eriodictyon, licorice, tar, wild cherry, salicylic acid, and potassium 
bromide in syrupy or glycerin menstruums. Expectorant tablets contain 
senega, Grindelia, aconite, squill, guaiac, ammonium bromide, and car- 
bonate. Alkaline extracts of the drug are commonly sold for admixture 
with syrup without precipitation of the resin. 

Power and Tutin 1 found that G. camporum contained 21-22 per cent 
of a complex resin to which its medicinal value is probably due. This 
resin was partly soluble in petroleum ether, and the portion remaining 
undissolved was nearly all taken up by ether, the first fraction being a soft, 
sticky, greenish mass, and the second a dark-colored resin. 

That portion of the Grindelia resins which were soluble in petroleum 
ether consisted to a large extent of a complex mixture of liquid acids, 
which were for the most part optically active, unsaturated cyclic com- 
pounds, some being oxyacids with apparently benzene nuclei. A very 
small amount of cerotic acid and apparently a trace of palmitic acid were 
present. A considerable quantity of chlorophyll was also present. The 
non-acidic portion of this fraction contained hentriacontane, C31H64, 
melting 68°, a new phytosterol, melting 166°, giving with sulphuric acid 
in a solution of chloroform and acetic anhydride, a rose color changing 
to violet, blue, dark green, and finally brown. It consisted, however, for 
the most part of a complex mixture of esters, presumably glycerides, the 
acids of which appeared to be similar to those which were present in the 
free state. 

The ether extract of the resin consisted to a very large extent of a 
mixture of amorphous products, but there were also present very small 
amounts of grindelol, a colorless crystalline substance, C23H38O4, melting 
256-257°, probably a phytosterol glucoside, and a yellow phenolic sub- 
stance, C14H12O5, melting 227-228°. 

That portion of the total resin insoluble in petroleum ether and ether 
amount to about 8 per cent and was nearly all dissolved by alcohol. 

An aqueous solution of an evaporated alcoholic extract of the drug 
contained free formic and butyric acids, tannin-like substances, ^-glucose, 
and protein. It gave precipitates with both neutral and basic lead acetates. 
No alkaloids nor saponins were detected. 

The characteristic odor of Grindelia is due to a volatile oil, and the 
presence of this ingredient is about the only distinguishing feature of 
the drug which can be used for its identification in complex mixtures. 
This evidence, backed by the identification of the readily detectable 
formic acid and the presence of a dark-green resin, may be considered 
as proof of the presence of the drug. 

1 Proc. A. Pha. A., 1905, 53, 193, and 1907. 



454 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 



ECHINACEA 

The root of the purple cone-flower has been recommended as an alter- 
ative and aphrodisiac, and may occur in preparations used for purifying 
the blood and for toning up the system. It also occurs in remedies intended 
to reduce swellings, varicose veins and abnormal growths. The freshly 
scraped root has been employed in the treatment of snake bites. 

Echinacea angustifolia (Brauneria a.) Composite, the narrow-leaved 
purple cone-flower is usually considered the source of the drug, but it is 
probable that the roots of E. purpurea, the purple cone-flower or black 
sampson, and E. pallida, the pale purple cone-flower, are collected and 
solid for the official drug without qualification. 

It is reported that large quantities of the root of Parthenium integri- 
folium, prairie dock or American fever-few, have been on the market at 
various times, apparently intended as a substitute for or adulterant of 
Echinacea. 

Heyl and Staley x report the following proximate analyses of angusti- 
folia and purpurea. 

E. angustifolia Per Cent E. -purpurea 

Moisture 10.90 10. 18 

Starch absent absent 

Pentosans 15 . 6, 15 . 1 15.6 

Fiber 24.77, 24.46 29.65, 29.51 

Protein 6.54, 6.96 5.31, 5.17 

Ash 7.76 .6.93 

Inulin 5.9 not determined 

Inuloid substance 5 . 94, 6 . 14 916 

Yield of Extract with: 

Ligroin 0.77 ■'. . . .0.93 

Ether 1 . 26, 1 . 18 1.61 

Alcohol 19.7, 19.94 18.28 

Examination of Alcohol Extract: 

Resin 1.84 2.00 

Sucrose 6.92 3.40 

Reducing Sugars 3.65, 3.52, 3.89 3.41 

Volatile Oil 0.04 

No alkaloid sufficiently basic to be extracted by the ordinary methods - 
is present, but the possibility of cholin or allied substances is not excluded. 

ARNICA MONTANA 

The flowers and the root of Arnica montana (Compositae) are used 
medicinally, and a tincture of the flowers is the preparation in common 
use externally for the relief of pain from bruises, sprains, etc. 

1 Am. J. Pharm., 86, 450. 



BOTANICAL DRUGS 455 

Arnica flowers are frequently adulterated and substituted by those 
of Calendula officinalis, Inula species, and Tragopogon pratensis. 

CALENDULA OFFICINALIS. MARIGOLD 

The ligulate florets of Calendula officinalis (Composite) are used for 
the same purposes as Arnica, and especially as a local remedy after surgical 
operations. As an internal remedy the drug has little use at present, 
though it was formerly used as a stimulant and diaphoretic. It will be 
found in certain popular local remedies intended to allay inflammation 
and reduce swellings, where it is mixed with Artemisia absinthium, Echi- 
nacea angustifolia, menthol, oils of lavender, sassafras, etc. 

Calendula contains a volatile oil and a gum which forms a transparent 
white mucilage with water, not precipitated by tannin. 

CARTHAMUS TINCTORIUS. SAFFLOWER 

Safflower or American saffron consists of the dried florets of Carthamus 
tinctorius (Compositse) . As a drug it was formerly employed for the 
same purposes as Calendula, especially to promote efflorescence in measles 
and other exanthemata, as a diaphoretic, and to dissipate incipient catarrh 
and muscular rheumatism. It is used to some extent as a component 
of emmenagogue mixtures with aloes, rue, and savine. 

THE CONDIMENTAL DRUGS 

There are several highly flavored vegetable products which are esteemed 
as flavoring agents in different classes of foods and have also an extended 
use in the compounding of medicines, where they functionate as flavor- 
ing agents, aromatics, or carminatives. 

Anise 

Anise seed, the fruit of Pimpinella anisum (Umbelliferse) is used as 
a carminative, for increasing the secretions of the mammary glands, and 
as a flavoring agent, in several well-known remedies and official mixtures. 
Both the ground fruit and the oil are used. 

The whole fruit is an important article of commerce, and it is often 
adulterated with small pebbles, earthy particles specially manufactured 
for the purpose, the fruits of grasses and rushes, and the fruit of Conium 
maculatum. The pebbles are easily detected by sprinkling a handful of 
the sample on the surface of water contained in a large beaker and rapping 
the sides of the container, when the heavier particles will sink to the bottom. 
Conium may be detected microscopically, by the mousy odor developed 
on warming with caustic alkali, and by the examination of an alcoholic 
extract of the drug for alkaloids. The ash of pure anise amounts to 7- 
10 per cent. The oil runs from 1.5-6 per cent. 



456 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Oil of anise enters into the composition of many different formulae. 
Liquid camphor compound contains anise oil, opium, camphor, and ben- 
zoic acid; liquid preparations of seneca and Spigelia sometimes contain 
oil of anise; and it is also present with rhubarb, licorice, and cardamon; 
and in the sarsaparilla mixtures with sarsaparilla, senna, potassium iodide, 
licorice, sassafras, and methyl salicylate. Fluid extract of orange com- 
pound contains extract of anise seed, orange peel, cloves, caraway, orris 
root, mace, cinnamon, and tonka. 

Oil of anise is present in cough lozenges and tablets, liver pills and 
infants' corrective tablets. 

Fennel 

Fennel fruit, from Fceniculum vulgare (Umbelliferae) and from the 
variety dulce (sweet or Roman fennel), is a carminative and aromatic 
drug, and used chiefly as a corrigent of senna, rhubarb, and other unpleas- 
ant tasting drugs. 

Fennel contains from 2-6.5 per cent of volatile oil, about 12 per cent 
of fixed oil, calcium oxalate and 7 per cent ash. The volatile oil contains 
50-60 per cent of anethol, 20 per cent fenchone, chavicol (an isomer of 
anethol), anise ketone, anisic aldehyde, anisic acid, d-pinene, and dipen- 
tine. The oil from sweet fennel contains no fenchone. Macedonian oil 
contains limonene, and phellandrene but no fenchone. 

The drug is adulterated with wheat screenings, undeveloped fruits, 
and various other umbelliferous fruits and dirt. The sophistications are 
detected microscopically and by the other tests given under anise. 

Oil of fennel is combined with opium and sodium bicarbonate in 
remedies for the colic of infants. The extract of the seed is one of the 
components of Warburg tincture. 

Caraway 

The fruit of Carum carvi (Umbelliferae) has an extended use as a 
flavoring agent, and medicinally as a remedy for the flatulent colic of 
infants. 

The most prominent constituent of the drug is the oil, which amounts 
to 5-7 per cent, and consists of about equal parts of d-carvone and d- 
limonene. The ash runs from 5-8 per cent. Calcium oxalate is a con- 
stant constituent of the fruit. 

Black caraway is the name given to the fruit of two plants belong- 
ing to an entirely different family, Nigella sativa and N. damascena 
(Ranunculaceae) . These seeds contain alkaloidal constituents and a 
volatile oil with a flavor like the wild strawberry. 

Caraway oil is one of the ingredients of fluid extract cardamom com- 
pound and of Spigelia and senna compound. It is also a component of 



BOTANICAL DRUGS 457 

certain pill formulae with aloes, soap, and confection of roses; rhubarb, 
colocynth, and Hyoscyamus; gentian, aloes, and rhubarb; aloes, scam- 
mony, myrrh, croton oil, and mercury mass. 

Coriander 

Coriander fruit from Coriandrum sativum (Umbellif erae) , is used 
medicinally as a stimulant and carminative. The chief use of the fruit 
is for the preparation of oil of coriander which is an important flavoring 
agent. 

Of the constituents, the most important is the oil, which amounts 
to 0.5-1 per cent and has a characteristic odor. The normal ash is about 
5 per cent. Calcium oxalate is present. 

Extract of coriander will be found combined with Stillingia, Chima- 
phila, Iris versicolor, Bicuculla, Sambucus, and Xanthoxylum berries 
in syrups and elixirs. It is also combined with senna, jalap, and rhubarb. 

Pimento 

Allspice or pimento is the fruit of Pimento officinalis (Myrtacese). 
While it is principally used as a condiment, it occurs in medicinal com- 
pounds as a stomachic, stimulant, and carminative. It is combined with 
pepsin, gentian, ginger, cardamom, and cinchona alkaloids. 

The fruit contains 3-4 per cent of a volatile oil, which consists of about 
60 per cent of eugenol. The ash runs from 4-7 per cent, but according 
to the standards of the Association of State and National Food and Dairy 
Departments it should not run over 6 per cent, with not more than 0.5 
per cent insoluble in hydrochloric acid. According to the same authorities 
the crude fiber should run not over 25 per cent, and the quercitannic acid 
not less than 8 per cent, calculated from the total oxygen absorbed by 
the aqueous extract. It should be mentioned at this point that determi- 
nations of tannins based on the absorption of oxygen are of little value in 
arriving at a conclusion as to the actual quantity of tannin-like substances 
present. The most common adulterants of powered allspice are cocoanut 
shells and cereal starches; other substances reported include clove stems, 
peas, olive stones, turmeric, pepper, Capsicum, and exhausted ginger. 

Tobasco or Mexican allspice is yielded by a variety of P. officinalis; 
Crown allspice by P. acris. 

Cloves 

Cloves are the dry undeveloped flowers of Caryophyllus aromaticus 
(Myrtacese), and in the ground state are used for condimental purposes, 
and in a small way medicinally for their stimulant and antispasmodic 
effect. The oil of clove is used as a flavoring, a corrective of griping 
purgatives, and in toothache remedies. 



458 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Volatile clove oil, which is the valuable constituent of the flowers, con- 
sists of about 70 per cent of eugenol with a smaller quantity of the sesqui- 
terpene caryophyllene. The oil runs from 9-20 per cent. The total ash 
ought not to be over 8 per cent, the crude fiber 10 per cent, and the food 
standards of the state officials demand not less than 12 per cent querci- 
tannic acid, determined by the empirical oxygen absorbed method. 

Ground cloves are subject to adulteration with clove stems, allspice, 
starch, exhausted ginger, and the other adulterants common to ground 
spices. 

Oil of cloves is combined with blackberry root bark and cassia and 
with rhubarb, cassia, and nutmeg. Powdered cloves is one of the ingredi- 
ents of blackberry cordial, which contains in addition nutmeg and cin- 
namon. The oil occurs with colocynth, aloes, scammony, and potassium 
sulphate; with strychnin, pepper, ipecac, and gentian; with aloes, Nux 
Vomica and Podophyllum resin, and similar combinations in pill formulae. 

Cardamom 

The fruit of Elettaria cardamomum (Zingiberacese), with its peculiar 
and characteristic flavor, is added to tonic and stimulant preparations 
chiefly as a flavoring agent. The commercial varieties are known as 
Malabar and Mysore cardamoms. 

The drug contains 4-5 per cent of volatile oil and from 4-6 per cent 
ash. 

Fluid Cardamom compound contains cardamom, caraway, cassia, and 
cochineal, and the British formula contains extract of raisin. Cardamom 
occurs in liquid aloes compound with myrrh, licorice, potassium carbonate, 
and saffron; in liquid cinchona, rhubarb, and gentian mixtures. Powdered 
cardamom is one of the ingredients of the compound cathartic vegetable 
pills and tablets with colocynth, Podophyllum resin, soap, scammony, 
and aloes; it occurs with gentian, ginger, Pimento, pepsin, and cinchona 
alkaloids; and with Capsicum and sodium salicylate. 

Cassia and Cinnamon 

The terms cassia and cinnamon are interchangeable commercially, 
but strictly speaking cinnamon is the inner bark of Cinnamonum zeylan- 
icum (Lauracese) of Ceylon, Sumatra, Java, and tropical Asia, or of C. 
louriria (Saigon cinnamon), and cassia is the bark of C. cassia, which 
comes from China, Indo-China and India. Cassia buds are the dry 
flower buds of the China cassia. Powered cassia often consists of a mix- 
ture of several varieties of bark, and the cheaper grades sometimes con- 
tain an admixture of the ground buds. 

While these products are of economic importance principally as condi- 



BOTANICAL DRUGS 459 

ments, they have a limited use medicinally as astringents and for their 
aromatic and flavoring properties. 

The ash of the Cinnamonum species should not be over 6.2 per cent. 
The important constituent is the volatile oil, which runs from 0.5-1 per 
cent in the Ceylon cinnamon and from .5-3 per cent in the cassia. The 
oil is composed principally of cinnamic aldehyde. Mannitol is present 
in the bark. 

The powdered drug may be adulterated with the usual spice adulter- 
ants, and in addition one may meet with the barks of other trees and 
epecially those species of Cinnamonium void of aromatic properties. 

Batavia cassia or Fagot cassia is the bark of C. burmanii. 

Powdered cinnamon is one of the ingredients of aromatic chalk powder, 
which also contains saffron, nutmeg, cloves, cardamom, and calcium car- 
bonate. The oil and the extract of cinnamon is often found combined with 
rhubarb and blackberry in liquid preparations. It occurs with aloes and 
iron sulphate in pills, and with methylene blue, salol, and sandalwood oil 
in soluble elastic capsules. 



CHAPTER XIV 
GUMS AND RESINS 

Gums and resins have played an important part in medicine since 
the early ages. To-day many of them are still used to a large extent 
for their therapeutic value and others are indispensable as mechanical 
agents. Whether used for the one purpose or the other their recognition 
is generally important. Gums such as acacia and tragacanth are often 
employed as emulsifying agents; rubber and colophony furnish the bases 
of plasters, and the chemist analyzing such preparations with a view to 
duplication must needs identify the kind and determine, at least approxi- 
mately, the amount of the mechanical agent present. Nearly all vege- 
table extracts contain more or less resin or gum, but the resins and gums 
of a comparatively few species have been described and their character 
determined. Those that have been investigated are generally extracted 
from the plant previously to their incorporation into medicine, and there- 
fore they are themselves commercial units, and as such are often the identi- 
fying features of the plants. Commercial gums and resins in the powdered 
form are subject to more or less adulteration and substitution. Standards 
have been adopted for most of the products recognized by the trade, and 
of late considerable attention has been directed toward the evolution of 
reliable tests for determining their quality. 

Gums and resins are very different chemically, but they are conven- 
iently considered under one heading and they are very often associated, 
the one class with the other. Gums belong to a class of complex poly- 
saccharide glucosides, while resins are composed of esters of aromatic 
acids with alcohols or resinotannols, resin acids, and indifferent bodies 
known as resenes. Gums are soluble in or swell up in contact with water 
and are not dissolved by alcohol. Resins are insoluble or but slightly 
dissolved in water; most of them are soluble or partly so in alcohol and 
ether. The resin esters are saponifiable. Naturally occurring mechanical 
mixtures of gums, resins, and volatile oils are classed as gum resins, oleo- 
resins, and balsams. Gum resins consist of variable mixtures of gums 
and resins, often with the presence of volatile oils (aromatic gum resins). 
Oleo-resins consist of resins and volatile oils, the former frequently being 
dissolved in the latter. Balsams consist of resins, aromatic acids, alco- 

460 



GUMS AND RESINS 461 

hols, and esters. The terms " gum," " resin," and "balsam " are often 
applied incorrectly from a chemist's standpoint. Trade customs over 
many years have brought about this condition, and the confusion of the 
commercial designation with the true chemical facts will often prove 
disconcerting to the analyst. 

CLASSIFICATION OF GUMS AND RESINS 

Gums 

Acacia. Soluble in water and precipitated by alcohol. 

Irish Moss and Quince Seed Gum. Soluble in water but not precipitated 

by alcohol. 
Agar. Soluble in water and partly precipitated by alcohol. 
Tragacanth. Swelling up with water and a portion dissolving. 
Indian Gum. Swelling up with water, but not dissolving, yielding acetic 

acid on hydrolysis with phosphoric acid. 

Resinous Substances (Lewton) 
True Resins 

Copal Group. Insoluble in the usual solvents unless themselves previ- 
ously fused. 

Dammar Group. More or less soluble in ether, chloroform, benzol, and 
acetone, but insoluble in alcohol. 

Sandarach Group. More or less soluble in alcohol. Guaiacum belongs 
to this group. 

Colophony Group. Soluble in alcohol. 

Benzoin Group. Soluble in alcohol, liberates benzoic or cinnamic acid 
when heated. 

Shellac Group. Form a turbid solution in alcohol. 

Gum Resins 

Inodorous Gum Resins. Yield an emulsion with water. Gamboge belongs 

to this group. 
Aromatic Gum Resins. Contain ethereal oils and yield an emulsion with 

water. 
Asafetida Group. Comprises asafetida, galbanum, ammoniacum, and 

opopanax. 
Myrrh Group. Myrrh, dibanum, and bdellium. 

Oleo-resins 
Varnish Group. 
Copaiba Group. Liquids. 

Turpentine Groyp. Soft resins, containing larger or smaller quantities 
of volatile oils. 



462 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Elemi Group. Soft resins rarely containing more than 10 per cent of 
ethereal oil. 

True Balsams 
Peru balsam, Tolu balsam, and liquid storax. 

GUMS 

Gums are chemically closely related to the glucosides. O'Sullivan 
has shown that they are built up of the residues of sugar molecules united 
by ethereal oxygen to organic acids. The sugars commonly evolved 
on hydrolysis are galactose and arabinose, but the acids usually differ 
in different gums, acacia containing arabic acid and tragacanth bassoric 
acid. 

Gums are soluble in, or swell up in contact with water, and are not 
dissolved by alcohol. They are amorphous, non-volatile, and colloidal. 
They are not fermentable by yeast. Their solutions are usually laevo- 
rotatory, but this is not. always the case, as Australian acacia is inactive, 
and gedda gum is dextro. 

They yield mucic acid on treatment with nitric acid. 

Natural gums are often admixture's of several gum compounds differ- 
ing in the number of sugar residues in their molecules. The testing of 
the gum components of complex mixtures is greatly complicated by the 
uncertain knowledge of the chemistry of gums and because of the sub- 
stitution and admixture of one gum with another, often through the 
ignorance of the crude drug merchant. The trade in powdered gums is 
large, and opportunities for sophistication are great and often resorted 
to. These conditions have been the cause of many erroneous reports 
concerning the chemical reactions and tests of gums. Tests for the pres- 
ence of tragacanth in ice cream have been worked out on Indian gum 
of an entirely different composition and properties than tragacanth. 
Mixtures of Indian gum and acacia have been sold for the pure acacia 
and used for the same purposes as the pure gum without detection on 
the part of the user. It is only within the last few years that tests 
have been devised for successfully proving the admixture of one gum 
with another. Those tests have been adapted to powdered gums as 
commercial commodities and not to mixed gums in pharmaceutical com- 
binations such as pills and emulsions. While it is possible to detect an 
individual gum in a pharmaceutical combination, it is doubtful if one 
would be justified in attempting to differentiate between several gums 
when together in such combination unless perhaps the component gums 
were equally balanced in amount. In such cases the personal experience 
of the investigator, resulting from the actual knowledge of how authentic 
gum specimens react, is of greater aid than printed directions. 



GUMS AND RESINS 463 

Acacia Gum (Gum Arabic) 

Several species of Acacia (Leguminosse) yield gums consisting prob- 
ably of calcium arabate and arabic acid. The gums of the best commercial 
qualities are designated gum arabic or gum acacia, those of less commercial 
value are the Senegal gums. 

Extensive researches on the sources, chemistry, and economic impor- 
tance of the Acacia gums have been conducted by the Wellcome Research 
Laboratories, Gordon Memorial College, Khartoum. The chief gum 
exported from the Sudan is that obtained in the Kordofan Province from 
the Acacia verek ('hashab), said to be identical with the Acacia Senegal 
from which Senegal gum is derived. 

As it ordinarily appears in commerce gum arabic occurs in rounded 
or ovoid tears or broken angular fragments. The color varies from white 
or yellowish white to amber. The pieces are usually translucent, but 
some of the angular fragments are often nearly transparent. When first 
collected the pieces are transparent and glassy, but. on exposure to the 
sun or artificial heat they dry and crack, the cracked pieces being nearly 
snow-white in color and very friable. Senegal gum is exposed to a less 
intense heat, and the gum itself is less brittle, consequently fewer cracked 
pieces and broken fragments are produced. 

The ash of good gum does not amount to over 4 per cent. 

The use of these gums for purely medicinal purposes is decidedly 
limited, being confined to soothing lotions and demulcents. They are 
important adjuncts in the preparation of pills, compressed tablets, troches, 
certain kinds of lozenges, and emulsions. 

The identification of gum acacia is not difficult. Its quantitative 
determination is seldom more than approximate. The value of a quanti- 
tative determination depends somewhat on the case in hand. If it is 
a question of accounting for the composition or of closely duplicating 
a given preparation it is important to know the kind and approximate 
amount of the gum present. 

Gum acacia is soluble in water to a clear liquid but is insoluble in 
alcohol and other organic solvents and the addition of alcohol to an 
aqueous solution of the gum precipitates the latter, when the alcohol 
amounts to 50-60 per cent. Tragacanth mixes with water to a pasty 
mass and a portion dissolves, but the appearance of the mixture is in no 
way comparable to that of acacia. Indian gum simply swells up with 
water to a transparent jelly. If the water is in large amount the mixture 
appears to be a solution, but it is not. 

When a 2 per cent solution of gum acacia is treated with 2J times its 
volume of 50 per cent alcohol and a 25 per cent solution of ferric chloride 
(acid free) is added a precipitate is produced. The deposit is often slow 
in forming. 



464 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Basic lead acetate solution throws out gum arabic as a curdy pre- 
cipitate. Neutral lead acetate does not produce a precipitate with solu- 
tions of the gums usually found in commerce. 

Copper sulphate followed by an excess of sodium hydroxide produces 
a precipitate which rises to the surface and does not dissolve on warming. 
Dextrin yields a precipitate which dissolves on warming, and the copper 
is reduced on boiling; however, nearly all samples of acacia have a vari- 
able cupric reducing action. The gum can be regenerated by dissolving 
the copper compound in dilute hydrochloric acid and adding alcohol to 
throw out the gum. 

These tests can be applied directly to a 2 per cent solution of the gum. 
When working with pharmaceutical mixtures it is advisable to separate 
the gum from the bulk of the material by digesting the material with water, 
filtering, and precipitating with an excess of alcohol. The precipitated 
gum can then be brought on to a filter, washed and dried, and then redis- 
solved in water to a 2 per cent solution. 

Emulsions should be mixed with a considerable volume of petroleum 
ether and then sufficient alcohol added to produce approximately a 50 
per cent aqueous menstruum beneath the volatile solvent when this sepa- 
rates. By separating the fight solvent which contains most of the oil 
and treating again, practically all of the oil can be removed. On adding 
a further quantity of alcohol to the hydroalcoholic layer, the gum ought 
to separate as a flocculent precipitate and can be tested as above described. 

Acacia gum contains an oxydase which causes the production of a blue 
color when an alcoholic solution of guaiacum is added to a solution of 
the gum. When a 5 per cent aqueous solution of the gum in cold water 
is treated with an equal volume of 1 per cent aqueous guaiacol and a drop 
of hydrogen peroxide added, a brown color develops. These tests may 
assist in the detection of acacia in the presence of other gums, but it is 
of no value in testing for it in pharmaceutical mixtures. The oxydase 
reaction was considered at one time to be limited to, and therefore char- 
acteristic of, gum arabic, but recent observations indicate that some of 
the cheaper grades of Smyrna tragacanths respond to the same tests. 
Jensen tested authentic specimens of the so-called Indian gums, from 
Sterculia urens and Cochlospermum gossypium, and obtained no reaction 
for oxidizing ferments. 

Acacia has a saponification value of about 10. 

Waters and Tuttle : have proposed the following method for the deter- 
mination of gum arabic : 

Fifty grams of copper acetate is dissolved in water, an excess of 
ammonia added, and the solution diluted to 1000 mils, using water and 
alcohol in such proportions that the final solution contains 50 per cent 
1 Dept. of Commerce, Bu. of Standards, Technologic Paper No. 67, page 13. 



GUMS AND RESINS 465 

of alcohol. For each determination a 50-mil portion of a gum arabic solu- 
tion, representing 0.25 gram of gum, is pipetted into a 250-mil beaker, 
an equal volume of alcohol added, and then 25 mils of the copper reagent, 
with constant stirring. The precipitate is allowed to settle, is filtered 
on a tared paper, washed with 50 per cent alcohol containing ammonia, 
then with 75 per cent, and finally with 95 per cent alcohol. It is dried 
to constant weight at 105°, ignited in a porcelain crucible, and the ash 
weighed. The amount of ash is deducted from the weight of the original 
precipitate and the difference called " net gum arabic." The amount 
of moisture in the gum originally taken for analysis must be allowed for. 
This is determined by drying in a current of Irydrogen at 105°. No 
allowance is made for the potassium and calcium, which forms an integral 
part of the gum. These may be to some extent retained in the precipi- 
tate and, therefore, be included in the ash. Any error that may be intro- 
duced by neglecting this is small and very much less than the error inherent 
in the method. 

This procedure can be applied to admixtures of gum arabic with 
tragacanth. The mixed gums should be digested with water, the solution 
made up to a definite volume, allowed to settle and an aliquot decanted 
for the determination. The application of this method to mixtures of 
acacia and Indian gum has not been determined. With dextrin it would 
apparently work successfully. 

If it is proposed to use this method for determining acacia in pharma- 
ceutical mixtures the gum should first be separated, as was recommended 
in making the qualitative tests. 

The gum of the mesquite tree of Texas occurs in tears and somewhat 
resembles acacia in its physical properties, but it does not yield the char- 
acteristic precipitates with lead subacetate and ferric chloride. 

Agar Agar 

Agar has recently come into prominence as a remedy for constipation. 
The commercial product consists of the stems of marine algae, of which 
the most important are Gelidium corneum, G. cartilagineum, Fucus 
amylaceus syn. Gracillaria confervoides, Euchema spinosum Ag, and cer- 
tain species of Tenax and Digartineae. 

Agar occurs in transparent strips of the thickness of straw, or in shorter 
and thicker yellowish-white pieces, odorless and tasteless. The aqueous 
solution gives no precipitate with tannic acid (absence of gelatin) and no 
blue color with iodine. A fragment of the material, however, under the 
microscope, stained with iodine, will show bluish black in places. 

Commercial agar usually contains diatoms, a characteristic form being 
Arachnoiliscus Ehrenbergii. To obtain the diatoms the organic matter 
may be oxidized with a mixture of nitric and sulphuric acid. These 



466 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

diatoms are disk-shaped and from 0.1 to 0.2 mm. in diameter. Spiculae 
of sponges are often present. 

The characteristic swelling and jellifying properties of agar are due 
to d-galactan or gelose. 

C. R. Fellers 1 has recorded an interesting research on agar. The 
average proximate analysis of a number of samples gave moisture 16.57 
per cent, protein 2.34 per cent, nitrogen-free extract 76.15 per cent, ether 
extract .30 per cent, crude fiber 0.80 per cent, ash 3.85 per cent, silica 
0.68 per cent. 

The average analysis of agar showed : 

Per Cent Per Cent 

CaO 0.92 As 2 3 0.000 

MgO 0.568 CI 0.22 

NaaO 0.25 I Present 

K 2 0.067 Pentosans 3.12 

FeaOs+AlaOs 0.55 Galactan 22.87 

Si0 2 0.83 Solution in water, 20° 19.00 

S0 2 2.645 Solution in water, 100° 96.20 

P 2 5 . 052 Protein in alcohol precipitate .... 1.12 

Mils excess N/1 HC1, per gram 0.029 

The solubility in cold water was determined by placing 5 grams of 
the air-dried substance in a flask containing 200 mils of water and allow- 
ing it to stand for eighteen hours with occasional shaking. 

The acidity was determined by treating 5 grams with 250 mils of water, 
heating until solution had taken place and then titrating 100-mil portions 
using phenolphthalein. 

The relatively high content of sulphur is no doubt due to the practice 
of bleaching with sulphur dioxide. 

The ether extract is an aromatic-scented, fight, amber colored, fatty 
substance of about the consistency of stearin. 

A high ash or silica content is indicative of an inferior product. 

Agar solutions are partly precipitated or rendered " tacky " with 
alcohol. Lead subacetate produces a precipitate, but neither lead acetate 
nor borax causes precipitation. 

Irish Moss 

Irish moss consists of the fronds of Chondrus crispus and Gigartina 
rnamillosa (Gigartinacese), marine growths, which are collected in large 
quantities. When fresh the color is purplish, but on drying the color 
disappears in part and as usually found in commerce Irish moss occurs 
in matted, horny, translucent masses of a yellowish or yellowish-white 
color. 

1 J. Ind. and Eng. Chem., 1916, 8, 1128. 



GUMS AND RESINS 467 

The mucilage is an important emulsifying agent and is often employed 
in lotions and jellies. Its presence may be suspected in any product of the 
type which does not yield a gummy precipitate with alcohol. It is often 
present in applications for sunburn, chapped hands, chafing, and similar 
discomforts and in such, aids in distributing the beneficial action of Ham- 
amelis distilled extract, boric acid, and glycerin. 

Irish moss softens and becomes gelatinous in cold water and yields 
a gummy constituent to boiling water. The solution is viscous and jelli- 
fies on cooling. It gives no precipitate with gelatin, lead acetate, borax, 
or alcohol, and is not colored blue by iodin. It gives a precipitate with 
lead subacetate. 

Quince Seed 

Quince seed contains a gelatinous substance which is readily soluble 
in cold water, and mucilage thus produced is a valuable emulsifying agent. 
It is employed in the preparation of lotions and creams. The seed con- 
tains a cyanogenetic glucoside, and under ordinary conditions this passes 
into the emulsion, and will be apparent through the hydrolysis and liber- 
ation of the benzaldehyde and hydrocyanic acid. Quince-seed emulsion 
is not precipitated by alcohol or borax, but it gives precipitates with lead 
acetate and subacetate. 

Gum Tragasol 

Gum Tragasol is the name given to a product obtained as a result of 
steeping locust-bean kernels with water. 

Tragacanth 

Tragacanth gum is obtained from shrubs of the Astragalus genus 
growing principally in Persia and Asia Minor. It enters commerce, as 
a rule, through ports in Persia, and from there is shipped to Russia, Great 
Britain, Turkey, India, and the United States. Previous to 1915 large 
shipments were handled through Hamburg. 

The exudations from the gum-bearing species of Astragalus resemble 
one another closely in physical and chemical characteristics. The whole 
gum usually occurs in ribbon-like bands or long linear pieces, flattened 
and often spirally twisted, varying in color from white to light brown. 
It has a horny appearance and is translucent and opaque when the pieces 
are dark-colored and thick. The bands are usually marked with ridges. 

The composition of the gum is complex. The literature contains the 
reports of several researches, but it is difficult to coordinate the results. 
O'Sullivan has determined the presence of starch, cellulose, nitrogenous 
matter, bassorin, and soluble gum. The soluble gum is built up with 
complex acids which he terms polyarabinan-trigalactan-geddic acids and 



468 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

which on hydrolysis yield arabinose. Bassorin, the insoluble portion, 
is of acid-like character and under the action of excess alkali yields two 
acids, alpha and beta-tragacanthan-xylan-bassoric acid, the former being 
readily soluble in water. 0' Sullivan found the formula of the alpha acid 
to be C24H34O20 • H2O, and on digestion with 5 per cent sulphuric acid at 
98° for twenty minutes it was hydrolyzed to tragacanthose and xylan- 
bassoric acid; the latter subsequently being resolved into xylose and 
bassoric acid by 5 per cent sulphuric acid. Bassoric acid is almost insolu- 
ble in cold water. It forms a jelly with alcohol. 

Tragacanth in the whole condition is recognized without difficulty. 
The finer grades are white and in thin pieces, the cheaper grades being 
darker in color and less uniform in appearance, some grades being almost 
entirely without the ridged and banded structure. The powder is often 
adulterated. Pure tragacanth when made into mucilage with water yields 
an opaque mixture which is neutral in reaction, froths when shaken with 
5 per cent potassium hydroxide, gives a blue color with iodin and pre- 
cipitates immediately with 2 volumes of alcohol. When the mucilage 
is mixed with an equal volume of 2 per cent borax solution no change in 
consistency is exhibited, and after standing for twenty-four hours it pours 
out as a homogeneous mixture without stringiness. When boiled with 
hydrochloric acid the mucilage develops a yellow to brownish tint with 
separation of a flocculent precipitate. High-grade tragacanth has a 
saponification value of 140-186. Its ash should not be over 3.5 per cent. 
It yields from 2-2.5 per cent acetic acid on hydrolysis with mineral 
acids. 

As a remedial agent tragacanth is valuable chiefly as an emollient. It 
is extensively employed as a mechanical agent in the preparation of emul- 
sions and pills. 

It is reported that certain lump tragacanths give reactions for oxidizing 
ferments which have been attributed to acacia alone. The procedure 
of the test has been detailed under the description of acacia. 

Fromme * recommends a method for determining the approximate 
percentages of acacia and tragacanth when mixed. Two grams of puri- 
fied sand is placed in a strong test-tube 16X150 mm., with 0.1 gram of 
the powder to be examined and the contents well mixed by shaking; 1 
mil of alcohol is then added, followed by 5 mils of water, and, after shak- 
ing well, 20 mils of an ammoniacal solution of copper oxide (cuoxam). 
The tube is then vigorously shaken and set aside for several hours. A 
similar test is carried out simultaneously with powdered tragacanth of 
known purity. On comparing the two tubes the height of the deposit 
will give a fairly good indication of the percentage of real tragacanth in 
the sample. 

1 Jahresbericht, Caesar and Lorenz, 1914, p. 28. 



GUMS AND RESINS 469 

The reagent is prepared by shaking copper turnings or powder with 
25 per cent ammonia until the solution becomes deep blue. 

Berlinia emini gum 

The gum from Berlinia emini, indigenous to German East Africa and 
identified by F. Mannich, resembles tragacanth. It occurs in horny 
brown opaque pieces with a slight peculiar odor and contains no starch. 
It yields an acid mucilage which is precipitated by lead acetate. 

Indian Gum 

There are several gums known as Indian gum, but none of these is 
obtained from any species of Astragalus. The name kuteera, katirah, and 
the same with many other spellings, has been applied to some of the Indian 
gums and to certain of the Astragalus products, the gums from A. hera- 
tensis and A. strobilifera, and it has no special significance and does not 
indicate the origin or proper classification of the gum. While it is possible 
that the Indian gum used so extensively in this country may vary as to 
its origin, the specimens examined in the whole condition correspond with 
samples of gum Sterculia urens submitted directly from India and from 
London. Furthermore, in a private report submitted from Bombay it 
is stated that S. urens is the source of this gum, and that it is used as a 
substitute for tragacanth in the government hospitals in Bombay. 

It occurs in striated hveguiar lumps, sometimes twisted, transparent 
or translucent and not in ribbony bands like tragacanth. As it reaches 
this country it often contains considerable bark which is bolted out before 
the powdered material is ready for the market. The powder is usually 
very white, rivaling in appearance that of the best grades of tragacanth. 
The bark contains characteristic stone cells winch pass into the powder, 
and serve as a means of identifying the source of the product. Tragacanth 
bark contains no substance of similar character. 

The powder of Indian gum forms a nearly transparent jelly with water, 

< swelling up to a considerable bulk and apparently dissolving, though, as 

a matter of fact, a small portion only is taken into solution. The aqueous 

solution is decidedly acid to litmus. It is unaffected by iodine solution 

and does not give a yellow color when warmed with alkali. 

When an aqueous mixture of this gum is boiled with dilute hydro- 
chloric acid, a clear solution with a marked pink color results. 

Indian gum reacts in a peculiar manner with borax; referred to at 
some length by Scoville, 1 which property is of value in detecting mix- 
tures. Tragacanth gives a smooth creamy mixture, Indian gum a thick 
1 Druggists' Circular, 1909, 116. 



470 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

slimy mass, often so gelatinous that it will not pour out of the container, 
this property being apparent even in presence of considerable amounts 
of tragacanth. The test is best performed by placing 2 grains of the powder 
in a 100-mil graduated cylinder, moistening with alcohol and adding 
about 50 mils water, shaking until a homogeneous mixture is obtained; 
2 grams of borax are dissolved in 50 mils of water, added to the jelly, the 
whole well shaken and allowed to stand overnight. When pure traga- 
canth alone is under examination, the resulting mixture will pour out of 
the cylinder without stringing, while if Indian gum is present a stringy 
mixture results. 

Indian gum evolves a relatively large amount of acetic acid when 
boiled with sulphuric or phosphoric acids. This property furnishes 
another ready means of detecting, as well as approximately estimating 
the quantity of the gum present in admixtures with tragacanth. Emery 1 
has determined that the average volatile acidity of the gum from S. urens 
is 15.79 per cent. His procedure for determining the volatile acidity 
is as follows: 

Treat 1 gram of the whole or powdered sample in a 700-mil round- 
bottomed flask, provided with a long neck, for several hours in the cold 
with 100 mils of distilled water and 5 mils of sirupy phosphoric acid until 
the gum is completely swollen. Boil gently two hours in connection with 
a reflux condenser, whereby a nearly clear, colorless solution is effected. 
A very small amount of cellulose substance will remain undissolved. 
Now subject the hydrolyzed product to slow distillation in a vigorous 
current of steam until the distillate amounts to 600 mils and the acid 
residue to about 20 mils. This should not be driven too far, however, 
otherwise there may be danger of scorching the nonvolatile, organic 
degradation products, with consequent possible contamination of the 
distillate. It has been found that a spray trap if used in connection 
with the flask containing the hydrolyzed gum, is effective in preventing 
traces of phosphoric acid being carried over into the distillate. Titrate 
with N/10 potassium hydroxide in connection with 10 drops of phenol- 
phthalein solution, finally boiling the liquid under examination until a 
faint pink color persists. Run a control on same amount of distillate 
obtained by a parallel operation, with omission of gum, but using like 
quantities of other ingredients and observing the same conditions as in 
the test. 

The published data on the Indian gums lack coordination. This may 
be due in part to the uncertainty of the botanical sources of the product. 
The information thus far obtained refers to two sources, Sterculia urens 
and Cochlospermum gossj^pium. The published data on both gums show 
that the two products are closely allied if not identical in composition. 
1 U. S. Dept. Agri. Bu. Chem. Circ. 94. 






GUMS AND RESINS 471 

Lemeland 1 and later Robinson 2 have conducted researches on a gum 
which they attribute to C. gossypium, but which is apparently the same 
as or closely allied to the gum from S. urens. The gum was obtained from 
a small deciduous tree of Northwestern Himalaya and central India. 

An examination of the gum furnished the following results: Moisture, 
22.72 per cent; ash, 4.64 per cent; the ash contains iron, calcium, and 
potassium as oxide and carbonate. 2.04 per cent of the gum is soluble 
in water, the solution possessing a rotatory power of +77.15°. Determi- 
nation of the galactans by Tollen's method gave 34.99 per cent (expressed 
as galactose). No arabinose or sugar other than ^-galactose could be 
isolated from the products; 22.59 per cent of pentosans, equivalent to 
25.64 per cent of pentoses, was found. The total quantity of sugar could 
not be determined, owing to the difficulty experienced in hydrolysing 
the gum, the highest result obtained being less than the sum of the pen- 
tose and galactose. On oxidation with nitric acid, 71.8 per cent of mucic 
acid (on the weight of gum used) was obtained. 

The gum examined by Robinson contained 15.5 per cent of water 
(loss at 100° C.) and 5.2 per cent of ash. It was investigated according 
to the method proposed by O'Sullivan. It probably consists of the tetra- 
acetyl derivative of a gummy acid to which the name a-cochlosperminic 
acid was given. This acid, probably C34H54O30, was isolated by treating 
100 grams of the gum with 2 liters of 5 per cent sodium hydroxide solution, 
and after standing for a long time, nearly neutralizing the mucilage with 
dilute hydrochloric acid, again allowing to stand for a few days, and then 
adding excess of strong hydrochloric acid solution. The solution was 
purified by dialysis, and the free gum-acid precipitated by alcohol and a 
small quantity of hydrochloric acid, washed with alcohol, and dried. It 
is a white granular substance, having a rotatory power (a) D = +57°; 
It gelatinized with water, but does not dissolve. On hydrolysis with 
dilute sulphuric acid, the gum yields 14.4 per cent of acetic acid, a gum- 
acid (gondic acid), and two sugars — xylose and hexose, possibly galactose. 
Gondic acid, C23H36O21, is soluble in water and is precipitated from solu- 
tion by alcohol as a white amorphous substance. It is an anhydride, 
and has the rotatory power (a) D = +97.7. 

RESINS 

The main constituents of resins may be divided into the following 
classes : 

1. Resin esters (resins) or their products. 

2. Resin acids (resinolic acids). 

1 J. Pharm. Chim., 1904, 20, 253. 

2 Chem. Soc. Trans., 1906, 89, 1496. 



472 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

3. Resenes, indifferent bodies of unknown classification. 
The aroma of resins is due in part to ethereal oils and liquid esters, 
among which cinnamic acid esters are important. 

1. Resin Esters 

The resin esters and resins are composed of aromatic acids of the ben- 
zoic and cinnamic series and resin alcohols (resinols and resinotannols) . 
Succinic acid, an aliphatic acid, occurs in amber. 

a. Benzoic acid, CeHsCOOH, (Peru and Tolu balsams, Siam benzoin, 

dragon's blood) 
Benzoylacetic acid, CH 2 (C 6 H5CO)COOH ; (Dragon's blood) 

.OH 
Salicylic acid, QqQa<^ (Ammoniacum) 

x COOH 

b. Cinnamic acid, C6H5CH==CHCOOH (Peru and Tolu balsams, 

Storax, Sumatra benzoin) 

/OH 
P-cumaric acid, CeH4\ (Aloes) 

\CH=CHCOOH 

/OH (1) 

Ferulaic acid, C6H3OCH3 , (2) (Asafetida) 

\CH-=CHC00H (4) 

/OH (1) 

Umbellic acid, C6H3OH , (3) with its anhydride 

\CH=CHC00H (4) 

Umbelliferone (Asafetida. Galbanum) 
Resin Alcohols. Resinols do not give a tannin reaction. Resinotan- 
nols are colored by iron salts. 

Resinols. 

Succinoresinol, C12H20O (Amber) 

Storesinol, (Storax) 

Benzoresinol, CioH 2 5(OH)0 (Benzoin) 

Chironol, C28H47OH (Opopanax) 

Resinotannols. 

Siaresinotannol, Ci 2 Hi 3 2 (OH) (Siam benzoin) 

Sumaresinotannol, Ci 8 Hi 9 3 (OH) (Sumatra benzoin) 

Peruresinotannol, C] 8 Hi 9 4 (OH) (Peru balsam) 

Toluresinotannol, Ci 7 Hi 7 4 (OH) (Tolu balsam) 

Galbaresinotannol, Ci 8 H290 2 (OH) (Galbanum) 

Ammoresinotannol, Ci 8 H 2 90 2 (OH) (Ammoniacum) 

Sagaresinotannol, C 2 4H 27 4 (OH) (Sagapenum) 

Dracoresinotannol, C 8 H y O(OH) (Palm dragon's blood) 



GUMS AND RESINS 



473 



Panaxresinotannol, C34H49O7 (OH) 

Xanthoresinotannol, C43H46O10 

Erythroresinotannol, C40H40O10 

Aloeresinotannol, C22H 2 505(OH) 

Asaresinotannol, C24H3s04(OH) 

Oporesinotannol, Ci2Hi302(OH) 
Some of the resinotannols yield picric acid when treated with nitric 
acid; ammoresinotannol and sagaresinotannol yield trinitroresorcin; gal- 
baresinotannol yields camphoric acid and camphoronic acid. When fused 
with potash, aliphatic acids are liberated and in some cases protocatechuic 
acid and resorcin. 



(Opopanax) 
(Yellow acaroid) 
(Red acaroid) 
(Aloes) 
(Asafetida) 
(Umb. opopanax) 



2. Resin Acids 




These acids all contain hydroxyl. 




Abietic acid, C20H40O2 


(Colophony) 


Pimaric acid, C20H30O2 


(Pine resin) 


Succinoabietic acid, C80H120O5 


(Amber) 


Sandaracolic acid, C45H66O7 


(Sandarach) 


/OCH3 
C4 3 H 6 i0 3 ^OH 

\COOH 






Callitrolic acid, C65H84O8 


(Sandarach) 


X)H 

C64Hg205\ 

XJOOH 






Trachylohc acid, CseHssOg 


(Copal) 


Isotrachylolic acid, CseHgsOg 


(Copal) 


Dammarolic acid, CseHsoOs 


(Dammar) 


Guaiacic acid, C20H26O4 


(Guaiacum) 


Guaiaconic acid, C19H20O5 


(Guaiacum) 


Copaibic acid, C20H30O2 


(Copaiba) 


Elemic acid, C35H46O4 


(Elemi) 


Masticinic acid, C20H32O2 


(Mastic) 


Acid, Ci 3 Hi 6 8 1 
Acid, C26H32O9 J 


(Myrrh) 


Acid, (C 9 H 13 02)„ 


(Bisabol myrrh) 


Boswellic acid, C32H52O4 


(Olibanum) 



3. Resenes 

The classification of these substances is uncertain. They are indif- 
ferent to the usual class reagents and are insoluble in potash. 
a-Panaxresene, C32H54O4 (Opopanax) 

/3-Panaxresene, C32H52O5 (Opopanax) 

a-Dammarresene, C33H52O3 (Dammar) 

j8-Dammarresene, C31H52O (Dammar) 



474 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Fluavil, C40H64O4 (Gutta percha) 

Alban, C40H64O3 (Gutta percha) 

a-Copal resene, C25H38O4 (Copal) 

Dracoalban, C20H40O4 (Palm dragon's blood) 

Dracoresene, C26H44O2 (Palm dragon's blood) 

Masticin, C20H32O (Mastic) 

Resene, C26H34O5 (Myrrh) 

Resene, (C29H470e)n (Bisabol myrrh) 

.Alibanoresene, (C^H^O)*, (Olibanum) 



METHODS FOR ANALYZING AND DETERMINING THE CONSTANTS OF 

RESINS 

When working with resins of known identity the analyst can proceed 
to determine the constants by the methods described below which have 
been found most applicable. When the resin is of uncertain identity, 
or in case it is a new and hitherto unreported body, its general character- 
istics must be ascertained before proceeding with the estimation of its 
constants. 

In order to arrive at a basis for future work the proximate analysis 
of the resin can best be obtained by following the procedure recommended 
by Tschirch. 

The sample is dissolved in a suitable solvent, such as ether or chloro- 
form, and shaken out successively with a 1 per cent solution of ammonium 
carbonate; a 1 per cent solution of sodium carbonate; a 0.1 per cent 
solution of potassium hydroxide; and a 1 per cent solution of potassium 
hydroxide. These reagents dissolve out the free resin acids, which can 
be recovered by acidulating with hydrochloric acid and shaking out with 
the proper solvent. The material remaining in the volatile solvent and 
which was inert to the alkaline solutions is distilled with steam, which 
removes any volatile substances and the solvent. The residue will con- 
sist of resin-esters and resenes. On saponification with alcoholic potash 
the acids liberated will go into the alkali, and on shaking up with ether 
the resin-alcohols and resenes are separated. The resin-alcohols are then 
separated from the resenes by acetylization or benzoyation. The identi- 
fication of the acids may be accomplished by resorting to the regular scheme 
of qualitative organic analysis and with these data in hand and an approxi- 
mate idea of the relative proportion of the resinous constituents, the proper 
methods of analysis can be selected. 

Resin-esters predominate in benzoin, Peru and Tolu balsams, storax, 
acaroid resins, aloes resins and dragon's blood (all so-called benzo-resins) 
and in the umbelliferous gum resins, ammoniacum, galbanum, sagapenum, 
asafetida, and umbelliferous opopanax. 



GUMS AND RESINS 475 

The resin acids predominate in the terpeno-resins from coniferous trees, 
colophony, copaiba, and Zanzibar copal. 

The resenes predominate in the burseraceous oleoresins, myrrh, oli- 
banum, bdellium, burseraceous opopanax, elemi, mastic, and the diptero- 
carpus products, Doona resin, dammar, and Manila copal. 

When working with natural drugs an average sample may be prepared 
by grinding at least 100 grams of the dry drug as finely as possible. Bal- 
sams should be well shaken and resins containing water should be freed 
from moisture and stirred up well together. Gum resins which are soft 
and difficult to pulverize should be cooled by immersion of the mortar 
in a good refrigerant. When the parcel is large the samples should be 
drawn from various parts of the bulk. 

A resin analysis may include the determination of the following data: 

Acid Value. The number of milligrams of KOH combined by the free 
acid in 1 gram of resin during direct or back titration. 

The acid value of the volatile portion is the number of 
milligrams of KOH combined by 500 mils of distillate obtained 
from 0.5 gram of gum resin by distillation with steam. 

Ester Value. The difference between the saponification value and the 
acid value. 

Saponification Value. (Hot — Cold). The number of milligrams of KOH 
combined by 1 gram of resin in hot or cold saponification. 

The total saponification value (fractional sapon.) equals 
the number of milligrams of KOH combined by 1 gram of cer- 
tain resins and gum resins on cold fractional saponification 
with alcoholic and aqueous alkali in succession. 

Moisture. 

Ash. 

Amount Soluble in Alcohol. 

Amount Insoluble in Alcohol. 

Amount Soluble in Other Solvents. 

Specific Gravity. 

Resin Value. The number of milligrams of KOH combined by 1 gram 
of certain resins and gum resins on cold saponification with 
alcoholic alkali by itself. 

Gum Value. The difference between the saponification value and the 
resin value. 

Acetyl Value. The difference between the acetyl saponification value 
and the acetyl acid value. 

Acetyl Acid Value. 

Acetyl Saponification Value. 

Acetyl Ester Value. 



476 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Carbonyl Value. The percentage of carbonyl oxygen in the substance 

taken. 
Methoxyl Value. The amount of methoxyl furnished by 1 gram of resin. 

Special determinations, such as cinnamein and resin esters in Peru 
balsam. 

In the case of soft resins and balsams the weighing should be con- 
ducted on a watch-glass or a closed weighing bottle, removing the desired 
quantity by means of a glass rod, and inserting the rod and adhering 
material into the receptacle for conducting the assay. 

In comminuting and reducing to a powder samples that are sticky, 
the end in view may be attained by storing the products in a cold place, 
which will usually render them hard and easily comminuted. Warming 
or heating in a drying oven should be avoided. All results should be cal- 
culated to the natural crude drug and not to goods dried at 100°. 

(The methods herein offered have been correlated and tested out by 
Karl Dieterich, to whom full acknowledgment is accorded.) 

Acid Value 

1. Direct titration. 

(a) When the sample is soluble in alcohol, chloroform and suitable 
neutral organic solvent. 

One gram is dissolved in a suitable solvent or mixture and 
titrated with N/2 or N/10 alcoholic potash using phenol- 
phthalein as indicator. 

(6) After the preparation of an alcoholic extract in the case of 
imperfectly soluble resins, the extract being used for titration. 
Applicable to gum resins, benzoin, storax. 
Same as above. The results may be calculated to 1 gram 
of the extract instead of the crude product. 

(c) Of the solution obtained by extracting a partially soluble 
resin with water and alcohol. 

Applicable to myrrh, bdellium, opopanax, and sagapenum. 
One gram of the finely ground resin is extracted by boning 
with 30 mils of water under a reflux for fifteen minutes, followed 
by the addition of 50 mils of alcohol 96 per cent, and reboiling 
for an equal period. After cooling the extract is titrated with- 
out filtration with N/2 alcoholic potash. 

2. Back titration. 

(a) In the case of completely (or nearly) soluble resins, free from 
esters, where the alkali combines with the acid and at the same 
time dissolves the resin. 

Applicable to dammar, sandarach, mastic, guaiacum, copal, etc. 
One gram of the finely divided (ester free) resin is left in con- 









GUMS AND RESINS 477 

tact with 25 mils of N/2 alcoholic potash and 50 mils of petro- 
leum ether in a stoppered flask for twenty-four hours or until 
solution has been carried as far as possible, and is then titrated 
back with N/2 sulphuric acid and phenolphthalein. 
(6) In the case of partially soluble — esteriferous but sparingly 
saponifiable — resins, where the alkali fixes the acid and at the 
same time dissolves the resin. 
Applicable to asafetida and olibanum. 

One gram of the finely powdered substance is left for twenty- 
four hours in contact with 10 mils of N/2 alcoholic potash and 
10 mils of N/2 aqueous potash in a stoppered flask. It is then 
mixed with 500 c.c. of water and titrated back. 

(c) In the case of resins that are only partially soluble and contain 
esters, an aqueous alcoholic extract being employed. 
Applicable to ammoniacum, galbanum, gamboge. 

One gram of the finely divided resin is boiled for fifteen minutes 
• under a reflux with 50 mils of water, after which 100 mils of 
strong alcohol are added and the whole boiled again for fifteen 
minutes. After cooling the whole is made up to 150 mils and 
filtered, 75 mils of the filtrate (equivalent to 0.5 of the sample) 
being treated for five minutes with 100 mils of N/2 alcoholic 
potash and then titrated back. 

(d) In the case of soluble resins which contain esters and are easily 
saponified. The natural drugs are used. Applicable to ben- 
zoin. 

Ten mils of N/2 alcoholic potash are allowed to act for five 
minutes on 1 gram of the drug, and then titrated back. 
3. By estimating the volatile acids. 

In the case of gum resins rich in ethereal oils. 
Applicable to ammoniacum, galbanum. 

0.5 gram of the sample is treated with a little water in a flask, 
and a current of steam is passed through, the flask being heated. 
The receiver contains 40 mils of N/2 aqueous potash, into 
which dips a tube from the condenser. Exactly 500 mils of 
distillate are collected, the condenser tube is washed out with 
distilled water and the whole titrated back. In this case the 
acid value gives the number of milligrams of KOH neutralized 
by 0.5 gram resin. 

Ester Value 

This is calculated by subtracting the acid value from the saponification 
value except in cases where the acid value has been determined as under 3, 



478 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

and where a resin value and total saponification value are present. In 
such event the ester value cannot be calculated. 

Saponification Value 

1. By the hot method. 

(a) In the solutions of completely soluble resins. 

Applicable to nearly all balsams and resins for which no special 
methods have been devised. 

On3 gram of the resin is dissolved in 25 mils of N/2 alcoholic 
potash, boiled at temperature of steam-bath for one-half hour 
under a reflux, diluted with alcohol and titrated back. 

(6) In the case of previously prepared alcoholic extract of a parti- 
ally or sparingly soluble resin. 
Applicable to gum resins, benzoin, storax. 
The same procedure as under a, except that an alcoholic solu- 
tion of the extract is taken, the results being calculated to 1 
gram of the crude drug and not of the extract. 

(c) In the case of gum resins partly soluble in water. 
Applicable to myrrh. 

The same procedure as under a except that the crude drug is 
taken after the addition of water to dissolve out the gum. 

2. By the cold method. 

(a) In the case of perfectly soluble resins with cold alcoholic potash 
and petroleum ether only. 

Applicable to Peru balsam, copaiba, benzoin, storax. 
One gram of the substance is treated in a stoppered 500-mil 
flask with 50 mils petroleum ether (sp. gr. .700 at 15° C.) and 
50 mils N/2 alcoholic potash. After standing twenty-four 
hours at room temperature, it is titrated back with N/2 sul- 
phuric acid. In some cases (Peru balsam) it is necessary to 
add 300 mils of water to dissolve precipitated salts. 

(b) In the case of imperfectly soluble resins. 

This procedure is a fractional saponification, including " resin 
value " and " gum value," alcoholic and aqueous alkali, with 
an addition of petroleum ether, being used in succession. 
Applicable to ammoniacum, galbanum, gamboge, dragons 
blood, lactucarium. 

Two samples, each of 1 gram, of the resin are powdered and 
suffused in separate 1-liter stopper flasks with 50 mils of petro- 
leum ether (sp. gr. 0.700 at 15° C.) followed by 25 mils of N/2 
alcoholic potash. After standing closed for twenty-four hours 
at room temperature, with frequent shaking, the one sample is 
shaken up with 500 mils of water and titrated back with N/2 



GUMS AND RESINS 479 

sulphuric acid; this gives the " resin value." The second 
sample is then further treated with 25 mils of N/2 aqueous pot- 
ash and 75 mils of water and left for another twenty-four hours 
with frequent shaking, being finally diluted with 500 mils of 
v/ater and titrated back. This gives the " total saponification 
value " the difference between this and the resin value being 
the " gum value." 

Acetyl Value 

In the method proposed by K. Dieterich for determining the acetjl 
value of resins, the substance is boiled under a reflux condenser, with 
an excess of acetic anhydride and a little anhydrous sodium acetate, until 
completely dissolved, or until it is evident that no further portion will pass 
into solution. The solution is poured into water, and the precipitate then 
ensuing is collected and extracted with boiling water until perfectly free 
from all traces of uncombined acetic acid. The insoluble residues left by 
copal and dammar are also treated in the same manner. The dried 
acetylized products are then tested for the acetyl, acid, ester, and saponi- 
fication values by dissolving 1 gram in cold alcohol and titrating with N/2 
caustic potash. The saponification is also effected with N/2 alkali for 
half an hour under a reflux condenser, and the product titrated back 
after cooling down and dilution with alcohol (not water). As in the case 
of fats, the difference between the acetyl-saponification value and the 
acetyl-acid value gives the true " acetyl value." 

Carbonyl Value 

The substance under examination is warmed with sodium acetate and 
an accurately measured quantity of phenylhydrazine chloride in dilute 
alcoholic solution. The excess of hydrazine salt not sharing in the reaction 
is then ascertained by eliminating the nitrogen by oxidation with Fehling's 
solution and collecting the gas in a measuring tube. The carbonyl value, 
i. e., the percentage of carbonyl oxygen in the substance taken, is ascer- 
tained by the formula 0=V—Vo , wherein V—Vo indicates the 

difference in the volume of nitrogen reduced to or 760 mm., and S refers 
to the weight of the substance in grams. 

Methoxyl value {Zeisel) 

As this method entails the use of apparatus and special precautions, 
it is considered preferable to repeat the author's own description in full. 
The Zeisel apparatus is made up as follows: A reflux condenser, fed 



480 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

with water at 40-50° C, is fitted with a small flask, the neck of which is 
provided with a lateral tube for the introduction of carbon dioxide. The 
upper end of the condenser tube is connected with a Geissler potash appa- 
ratus which is charged with amorphous phosphorus suspended in water, 
and is placed in a water-bath kept at about 50-60° C, its purpose being 
to free the current of alkyl-iodide vapor passing through from hydriodic 
acid and iodine vapor. The alkyl iodide is led into a 4 per cent solution 
of silver nitrate in two successive flasks, the whole being generally retained 
and converted into silver iodide in the first one. In performing the experi- 
ment, the substance to be examined for methoxyl is heated along with 
10 c.c. of hydriodic acid of sp.gr. 1.68, CO2 being passed through the appa- 
ratus. The experiment is complete when the liquid in the first flask has 
become clear above the deposit of silver iodide, and the silver iodide is 
then determined by gravimetric means. 

For ordinary analyses it is sufficient to use 50 mils of the silver nitrate 
solution in the first flask, and 25 mils in the second, after acidification 
with a few drops of nitric acid free from nitrous acid. After the reaction 
is terminated — ZeisePs conditions being otherwise maintained through- 
out — the clear liquid above the silver iodide is poured off into a 250-mil 
measuring flask. The silver nitrate solution in the second flask is diluted 
with water and poured into the same measuring flask, the contents of 
which are thereupon made up to the mark with water, agitated well, and 
passed through a folded filter into a dry vessel. 

For the titration, 50 or 100 mils of the filtrate are used, after suitable 
acidification with nitric acid (free from nitrous acid) and an addition of 
ferric sulphate solution. 

SEPARATION OF RESIN ACIDS AND FATTY ACIDS 

In the case of a fatty acid adulterated with resin, about 0.6 gram of 
the substance is dissolved in 20 mils of 95 per cent alcohol. To this 
solution is added a trace of phenolphthalein, and a solution of alcoholic 
potash is run in, drop by drop, from a burette, with continued stirring, 
until the indicator has assumed a dark red color, characteristic of alkalinity. 

After adding one or two drops of the potash solution in excess, the 
flask containing the liquid is placed on the water-bath and the contents 
boiled for ten minutes. When cold, the whole is poured into a 100-mil 
test-tube, the flask washed with ether, and — the whole being made up to 
100 mils with this solvent — the tube is corked and shaken up thoroughly. 

Next, 1 gram of finely divided silver nitrate is introduced and shaken 
up well for ten to fifteen minutes, until the flocculent deposit of silver 
st ear ate or oleate has collected together at the bottom of the tube. Then 
50-70 mils of the clear liquid are removed by means of a pipette, and 



GUMS AND RESINS 



481 



transferred to another 100-mil test-tube, where a further small quantity of 
silver nitrate is added to remove the fatty acid still in solution. The clear 
liquid is then mixed with 20 mils of dilute hydrochloric acid (one-third 21 
per cent HC1 and two-thirds water) ; an aliquot part of the supernatant 
ethereal solution is evaporated in a platinum basin, the residue — dried 
in the steamer — being resin, accompanied by a little oleic acid. Direct 
experiment has shown that, under these conditions, 10 mils of ether 
retain on an average 0.00235 gram of oleic acid, so that the result of the 
analysis may be corrected by means of this coefficient. The method is 
applicable to the determination of resin in linseed oil, soap, etc. 

CLASSIFICATION OF INDIVIDUAL RESINOUS SUBSTANCES 



Resins 


Oleo Resins 


Balsams 


Gum Resins 


Aloes 


Canada Balsam 


Peru 


Ammoniacum 


Anime 


Copaiba 


Tolu 


Bdellium 


Amber 


Cubeb 




Euphorbium 


Benzoin 


Gurjun Balsam 




Galbanum 


Colophony 






Gamboge 


Dragon's Blood 






Lactucarium 


Elemi 






Myrrh 


Guaiacum 






Sagapenum 


Jalap 






Asafetida 


Kino. Red Gum 






Olibanum 


Labdanum 






Opopanax 


Mastic 








Sandarach 








Scammony 






Chicle 


Shellac 






Gutta Percha 


Storax 






Caoutchouc 


Tacamahac 








Thapsia 








Turpentine 








Turpethura 








Podophyllum 









Of these Benzoin, Storax, Peru, and Tolu Balsams are treated more 
conveniently in the discussion of aromatic acids. Jalap and Scammony 
have been treated, and Podophyllum and Cubeb have also been described. 

Of the remainder the most important from the point of view of medical 
usage are Guaiacum, Kino, Turpentine, Copaiba, Ammoniacum, Gam- 
boge, Lactucarium, Myrrh, and Asafetida. The others have but a limited 
use as therapeutic agents or are employed only for their mechanical effect 
in the preparation of plasters, varnishes, and coverings for wounds and 
abraded surfaces and for coloring mouth washes. 



482 GLUCOSIDES, GLUGOSIDAL DRUGS AND NATURAL DRUGS 

GUAIACUM RESIN 

Guaiacum resin is obtained from the wood of Guaiacum officinale and 
G. sanctum (Zygophyllacea?) . These trees grow in Cuba and some of 
the other West India Islands, the Bahamas, Hayti, and Jamaica. The 
wood is used medicinally for the same purposes as the resin. It is a hard, 
heavy wood, and known commercially as lignum vilce. 

The resin occurs in irregular or somewhat globular masses of a glassy 
luster and resinous fracture. The color is deep greenish brown or dark 
olive on the outer surface; the internal color which has not been exposed 
to the air is reddish brown or hyacinth, diversified with shades of various 
colors. It is brittle and presents a shining, glassy surface when broken. 
The taste is not perceptible at once, but soon becomes acrid and leaves a 
permanent sensation of heat and pungency. 

Guaiacum is employed as an alterative, stimulant, diaphoretic, and 
anti-rheumatic. It is dispensed in the form of a plain tincture and with 
aromatic spirit of ammonia. Liquid sarsaparilla compound contains guai- 
acum with sarsaparilla, sassafras, licorice, and mezereon bark. Compound 
tincture of guaiac or Dewer's tincture contains guaiac, potassium car- 
bonate, and pimento, and is a remedy for suppressed menstruation. 

Some of the pill and tablet formulas which may be mentioned include 
the N. F. Antimony Comp. (Plummer pills) which contains guaiac, calomel, 
sulphurated antimony, and castor oil, it will also be found combined with 
copaiba, cubeb, and ferric citrate; with calomel and opium; with aloes, 
sulphur, Podophyllum, and frangula; with potassium iodide, Phytolacca, 
colchicin, and digitalin (anti-rheumatic); with salicylic acid, sodium 
bicarbonate, and Colchicum ; with cantharides, aloes, and ferrous sulphate 
(emmenagogue) ; with ammonium chloride, licorice, and Hydrastis 
(throat); with senega, squill, aconite, Grindelia, ammonium carbonate, 
and ammonium bromide; with terpin hydrate, opium, wild cherry, and 
belladonna. It is dispensed alone in lozenges and may be found com- 
bined with Sanguinaria. 

Guaiacum mixture is an emulsion of guaiac with tragacanth, sugar, 
and cinnamon water. 

Guaiac occurs as the crude resin in which condition it is mixed with 
fragments of wood and bark and dirt; as the purified resin and in the form 
of tears. The pure resin consists of guaiacum resin (C20H23O3OH) ; 
guaiaconic acid (C2oH 2 20 3 (OH) 2 ); guaiacic acid (C 2 iHi 9 04(OH) 3 ); guai- 
acol and guaiacum yellow (C20H20O7). It often contains up to 9 per cent 
of gum. 

Pure resin is almost completely soluble in alcohol, chloroform, and 
acetic ether, and all but about 10 per cent is soluble in ether and benzol, 
though Evans reports commercial samples running as high as 11.7 per cent. 



GUMS AND RESINS 483 

Pure resin has only a slight amount of ash. The acid value may run from 
89-98, but Dieterich records the tears as running from 72-76, and Evans 
finds 45-56. The methoxyl values have been reported from 73.8-84. 
' Dieterich has determined the acetyl values and found 

Acetyl 

Acid Value Ester Value Sapon. Value 

Purified 13.57-14.89 149.33-149.75 163.22-164.22 

Commercial Crude .... 45 . 84-53 .15 121 . 75-129 . 16 167 . 59-192 . 44 

Dieterich recommends the following procedure for determining the 
acid value. One gram of the resin is suffused with 10 mils N/2 alcoholic 
potash and 10 mils N/2 aqueous potassium hydroxide, and left for twenty- 
four hours in a glass-stoppered flask. After adding 500 mils of water 
the liquid is titrated back with N/2 sulphuric acid and phenolphthalein. 

Adulteration with colophony is indicated by a high acid value and the 
adulterant can be identified by the Storch-Morawski test applied to the 
abietic acid, which is first separated by treating an alcoholic solution with 
an excess of potassium hydroxide. 

Guaiac is adulterated with a similar product of yellowish-brown color 
known as Peruvian guaiacum (Guaiacum peruvianum odoriferum). 
Admixture with this resin may be detected, according to Hirschsohn, 
by treating a chloroformic solution with bromin fumes, which produce 
a red color, whereas pure guaiac solutions turn blue. 

An alcoholic solution of guaiac gives a blue color with tincture of ferric 
chloride, manganic and silver salts, nitric acid, chlorin, gluten, mucilage 
of acacia, milk, and with hydrocyanic acid, followed by copper sulphate. 
Citric acid prevents the production of the color with ferric salts, and egg 
albumen reduces the sensitiveness. It dissolves in cold concentrated 
sulphuric acid to a rich claret-colored solution which on dilution deposits 
a lilac-colored precipitate. Mammalian blood-stains, moistened with the 
tincture and followed by a few drops of dilute irydrogen peroxide, become 
blue in color. 

When analyzing a medicine guaiac will remain undissolved when an 
evaporated alcoholic extract of the product is treated with water. On 
treating the residue with chloroform, the guaiac will dissolve and the solu- 
tion may be filtered from any insoluble material, evaporated, and the 
residue dissolved in alcohol. Strips of clean white filter paper should be 
moistened with this tincture and when nearly dry exposed individually 
to the fumes of nitric acid and chlorin, which should produce blue colors 
in the presence of guaiac. Other strips should be moistened with tincture 
of ferric chloride and with hydrocyanic acid and copper sulphate. Drops 
of the tincture should be added to gluten, mucilage of acacia, and milk, 



484 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

all of which should give positive reactions. A test should be obtained 
with blood-stains using the tincture followed by hydrogen peroxide. 

In the absence of other resinous drugs the proportion of guaiac in a 
medicine can be determined by extracting the powdered substance with 
alcohol, or treating an evaporated liquid mixture with alcohol. In either 
case the alcoholic extract thus obtained should be concentrated and poured 
into an excess of water, which will precipitate the resin. The liquid is 
decanted through a filter and after washing with water the resin is dis- 
solved in chloroform and the chloroformic liquid shaken with dilute sul- 
phuric acid. If the acid removes any basic substances the shaking is 
continued with successive portions of acid until a test with Mayer's reagent 
produces no precipitate. The chloroform is then washed with water, 
filtered into a tared dish, evaporated and the residue weighed, 

KINO 

The resins and gum-resins known as " Kinos " are obtained from a 
number of different sources. The resin which is known to the pharmacist 
as kino is obtained from Pterocarpus marsupium (Papilionacese) . Kinos 
from Eucalyptus rostrata and other species of Eucalyptus are known as 
" red gum." 

Kino is employed as an astringent. It is dispensed as a tincture and 
in pills and tablets, combined with camphor, opium, and Capsicum; 
diarrhea tablets contain kino, opium, camphor, bismuth subnitrate, sodium 
bicarbonate, and mercury with chalk. 

Red gum is a component of astringent lozenges and mouth washes, 
and is also used in seasickness. 

Kinos consist of dark-red or reddish-black resinous appearing brittle 
masses or granules, having an astringent taste and imparting a red color 
to the saliva. They dissolve in part or swell up in the presence of water, 
and the Pterocarpus kino is soluble in alcohol. They also dissolve in 
alkalies, but are nearly insoluble in ether. 

The resin of Pterocarpus marsupium contains a large porportion of a 
tannin known as kino-tannic acid, ash, kino-red, pyrocatechuic acid, and 
woody trash. The alcoholic solution tends to gelatinize. Aqueous solu- 
tions give a green color with ferric sulphate, changing to violet on the 
addition of alkali carbonates or acetates. Ferric chloride produces a 
green precipitate which turns purplish red in the presence of alkalies. 
Dilute mineral acids throw out a flocculent precipitate. The aqueous 
solution is precipitated by gelatin, and the soluble salts of silver, lead, 
mercury, and antimony. 

Commercial kinos differ in their properties. Good kino should show 
from 90-98 per cent soluble in 90 per cent alcohol, 85-95 per cent soluble 



GUMS AND RESINS 485 

in water, 50-60 per cent tannin, not over 3 per cent ash and from 8-18 
per cent moisture. The U. S. P. is considerably less rigid in its solubility 
requirements and provides for a product which should yield not less than 
45 per cent to alcohol and not less than 40 per cent to boiling water. 

Eucalyptus kino is claimed to contain gallic acid and catechin in addi- 
tion to the other constituents reported in Pterocarpus. Thum found that 
less than 20 per cent was soluble in boiling water and that a solution of 
any strength would gelatinize unless glycerin was present 

THAPSIA RESIN 

Thapsia resin is obtained from Thapsia garganica (Umbellif era?) . It 
is a strong counter irritant and is sometimes used in plasters. The resin 
and the root of the plant when handled cause intense itching of the hands 
and exposed membranes. 

The blistering substance crystallizes and is reported to have a melting- 
point of 87° C. By successive extraction with alcohol and ether two resins 
have been separated, the former giving a scarlet color with sulphuric acid 
and the latter a blue color. 

Dieterich has developed a procedure for examining thapsia resin which 
avoids the dangerous consequences which would result by operating under 
ordinary conditions. 

About 1 gram of Thapsia resin is mixed with a sufficient amount of 
pure sand, and the crumbled mass placed in a Schleicher & Schull cartridge, 
the weight of cartridge + sand + resin being noted, as well as that of the 
cartridge + sand, and of the resin by itself. The whole is then treated, 
in a Soxhlet extractor, with petroleum ether for three hours, and, after 
cooling down, the cartridge is dried in the oven at 80° C. until no further 
odor of petroleum ether is discernible; longer drying must be avoided in 
view of the moisture-content of the resin. The cold petroleum ether 
extract is next treated with 20 mils of alcoholic N/2 caustic potash and 
boiled for half an hour under a reflux condenser, the apparatus being 
tightly stoppered. After cooling, the saponification value of the portion 
soluble in petroleum ether is determined by the usual method and the 
results are referred to 1 gram. 

The percentage soluble in petroleum ether is found, indirectly, by 
calculation, from the loss in weight of the aforesaid cartridge, and expressed 
as a percentage. The cartridge is then replaced in the extractor, and, 
after charging the bottom flask with 20 mils of alcoholic N/2 caustic potash 
and 50 mils of alcohol, is extracted for two hours longer. The alcohol 
serves as the extracting reagent, while the underlying alkali immediately 
saponifies the dissolved substances. After two hours the whole apparatus 
is cooled, and the cartridge is then dried at 100° C. until constant. 



486 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The extra loss in weight, calculated m percentages, gives the value 
of the portion soluble in alcohol; the residue, which is easily calculated by 
deducting the weight of cartridge + sand from the total weight of cart- 
ridge + sand + resin, expresses the value, insoluble residue. 

The saponification liquid in the flask is titrated and — calculated to 
1 gram — gives the saponification value (hot) of the portion soluble in 
alcohol. 

The total saponification value (hot) of the original resin is found 
by saponifying 1 gram of the resin with 25 mils of alcoholic N/2 potash, 
under a reflux condenser, and titrating back when cold. 

The following data were obtained on authentic thapsia: 

Per Cent 

Moisture 7.43- 10.33 

Ash 0.16- 0.415 

Soluble in petroleum ether 19 . 28- 25 . 67 

Soluble in alcohol 83 .46- 89.32 

Total Saponification value 336 . 33-384 . 47 

Thapsia is adulterated with euphorbium and the resins of Thapsia 
villosa, which contains acrid substances but is milder in its action. 

TURPENTINE 

The various species of Pinus (the pines), Picea (the spruces), Abies 
(the firs), Tsuga (the hemlocks), and Larix (the larches), of the Pinacese 
yield oleoresinous exudations to which the name turpentine is gh r en. 

The pines which furnish the greater part of the turpentine gathered 
in the United States are P. palustris, the long-leaved or Georgia pine; 
P. taeda, the loblolly or old field pine; P. echinata, the yellow or spruce 
pine, and P. heterophylla, the Cuban or swamp pine. 

The exudation from Abies balsamea, the balsam fir, is known as Canada 
balsam, but the balsams from A. fraseri and Tsuga canadensis, the hem- 
lock, are collected for this product. A. excelsa yields Burgundy pitch. 

Venice turpentine is an exudation from the European Larix decidua. 

Russian turpentine is obtained from Pinus sylvestris, the type species 
of the Pinus, and which is regarded by some authors as belonging to a 
distinct genus from the several species of Pinus indigenous to the United 
States. 

Chian turpentine is obtained from Pistacia terebinthus and Strasburg 
turpentine from Abies picea. 

Turpentine consists of a complex mixture of turpentine oil, resin acids, 
colophony, and other substances. Turpentine oil, the limpid volatile 
fraction of the oleoresin, consists largely of d-pinene. Exception to this 
general statement occurs in the case of the French oil from P. pinaster 
(P. maritima). Camphene also occurs in turpentine oil. 



GUMS AND RESINS 487 

Turpentine or more often the oil of turpentine is used externally as 
a rubefacient and counter-irritant and will be found with various other 
substances in liniments and embrocations. Internally it is employed 
as an anthelmintic, stimulant, hemostatic, emmenagogue, and antiseptic. 

It will be found in emmenagogue pills, in gonorrhea mixtures, cough 
tablets and elixirs and combined with copaiba and oil of cubeb in gelatin 
capsules. It is employed in remedies for dropsy as a diuretic, for tape 
worm, for rheumatism, and as an antidote for phosphorus poisoning. 

In many cases Venice turpentine will be found functionating in place 
of the Pinus turpentine 

Chian turpentine has been employed in the treatment of cancer. 

The turpentines are liquid when freshly gathered, but soon become 
thick on exposure, due to loss of volatile oil and oxidation. They soften 
on heating and burn with a smoky flame. They dissolve in the ordinary 
volatile solvents and in the fixed and volatile oils. When taken internally 
or applied to the skin they impart a violet odor to the urine. 

The acid value of turpentine ranges from 100-145. The ester value 
is reported from 2-60, the saponification value 108-180. Venice turpen- 
tine has a lower acid value, 60-80, and saponification values as low as 81 
are reported, refractive index 1.518-1.521. Kremers reports the follow- 
ing rotation figures: 

(a) D oleoresin P. palustris — 13.665° 

(a) D oil P. palustris +23.93° 

(a) D oleoresin P. cubensis —32.428° 

(a) D oil P. cubensis + 9.6° 

Dieterich reports the following acetyl value for ordinary turpentine: 
Acetyl: 

Acid value 123.75-125.55 

Ester value 62.32-93.79 

Saponification value 187-87-217.04 
For Venice turpentine: 
Acetyl: 

Acid value 69.87-72.19 

Ester value 109.08-118.67 

Saponification value 178.95-190.86 

The admixtures of ordinary turpentine with Venice turpentine may 
be recognized by a consideration of the acid, saponification, and acetyl 
values. 

Pinus turpentine when added in small quantity to strong ammonia 
water produces a milky mixture which will set to a jelly when the propor- 
tion is about 1-5. Venice turpentine, under similar conditions, does not 



488 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

distribute itself; the liquid remains clear, and subsequently the turpen- 
tine is converted into a semi-solid, colorless, opaque mass. 

Pinus turpentine sets into a hard mass when mixed with 20 per cent 
of its weight of calcium hydroxide. Venice turpentine does not set immedi- 
ately when mixed with this reagent. 

Haarlem Oil 

This product formerly enjoyed an enormous sale in the United States. 
It is an old remedy and the genuine Haarlem oil gets its name from the 
town in which it was first manufactured in Holland. Several formulas, 
more or less similar, have appeared in the market, all bearing the name 
Haarlem oil. The original claims for this mixture were about the most 
far-reaching of any claims that have been attached to any remedy in 
modern times, and after reading them the patient might believe himself 
to be the possessor of the panacea of all evil and the golden touch of old 
King Midas. The principal ingredients were linseed oil, which had been 
boiled with sulphur, and turpentine. 

Chian Turpentine 

The specific gravity is reported 1.050 but varies with the percentage 
of volatile oil. It is readily and almost completely soluble in the ordi- 
nary volatile solvents and according to E. Dieterich has acid value d. 47.13- 
^8.53;- ester value 19.13-21.47; saponification value, h. 66.26-70.00. 

Abietic Acid, C20H40O2 

Abietic or sylvic acid is the chief constituent of colophony or common 
rosin, though it has been reported that some samples of authentic identity 
contained none. Colophony is the anhydrous residue left on the dis- 
tillation of the turpentine obtained from different trees of the Pinus 
family. When pure, abietic acid is a white crystalline substance melting 
182°, (156-162° Cohn), insoluble in water but dissolving in alcohol, ether, 
benzol, and glacial acetic acid. When treated with strong ammonia 
it is converted into a gelatinous mass which dries to a solid resin, readily 
soluble in water. Copper abietiate is soluble in ether. 

In analytical work abietic acid is seldom obtained pure, but in admix- 
ture with the other rosin acids. They are easily removed from ethereal 
solution by shaking with caustic alkali and then removed from the alka- 
line liquid by adding excess of acid and shaking out with ether. The 
ether on evaporation leaves a residue of free acid which can be separated 
from phenols or any moderately soluble acids if these are present, by 
washing with boiling hot water. The rosin acids after the above treat- 
ment can be subjected to the Liebermann-Storch (Storch-Morawski) 



GUMS AND RESINS 489 

reaction. A portion of the residue is dissolved in warm acetic anhydride 
and after cooling, sulphuric acid (1-1 by volume) is allowed to flow into 
the solution, producing a reddish-violet color. 

Kauri resin gives a deep violet-red color changing to brown; amber 
and East India and black dammar resins, deep wine red changing to brown; 
Manila, pontianac, and Borneo resins, dark brown, Batavia, and Sing- 
apore dammar resins, deep wine red which does not change on standing. 
Some specimens of Manila give a reaction similar to that of abietic acid. 

The copper acetate test for abietic acid is obtained by dissolving the 
resin in alcohol, transferring to a separatory funnel and adding an equal 
volume of petroleum ether. When mixed by agitation, water is added and 
the whole shaken for thirty seconds. After separating, the aqueous layer 
is drawn off and the petroleum ether washed with water until both layers 
are clear. Thirty mils of a J per cent solution of copper acetate are added, 
shaken and the appearance of a green color in the petroleum ether indi- 
cates abietic acid. 

Rosin is used as the adhesive agent in certain forms of plaster and the 
general directions for handling this class of products qualitatively is given 
in detail in my work on Qualitative Analysis. 

One well-known plaster in general use consists of rosin and tartar 
emetic. If it is desired to determine the latter ingredient, the plaster 
or a known proportion of it is treated with absolute ether, which dissolves 
the resin and leaves the tartar emetic behind. The ether solution is 
filtered off and the container and filter washed with ether, until free of 
rosin. The tartar emetic is then dissolved in water and the antimony 
precipitated by hydrogen sulphide and the determination finished as 
detailed under Antimony. 

CANADA BALSAM 

Canada balsam is a clear, pale yellow (almost greenish) and slightly 
fluorescent viscid liquid, with a pleasing odor and bitter taste, and solidi- 
fying on exposure to the air. It is completely soluble in chloroform, ben- 
zol, and acetic ether, largely soluble in ether and oil of turpentine and 
partly soluble in alcohol and petroleum ether. It solidifies when mixed 
with magnesia and water. Its acid value is reported from 81.3-86.8; 
ester value 4.54-13.1; and saponification value, hot 89.43-95.76; refrac- 
tive index 20°, 1.5194-1.523. 

Dieterich, quoting Bonastre, gives the composition of Canada balsam 
as follows: 

Per Cent 

Lsevorotatory ethereal oil 18.6 

Resin soluble in alcohol 40 . 

Resin sparingly soluble in alcohol 33 . 4 

Caoutchouc 4.0 

Bitter principles, extractives, trace of acetic acid 4.0 



490 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Tschirch, working on more modern lines, has isolated resinol acids 
standing in a certain relationship to abietic and pimaric acids. 

Canada balsam is used in chronic bronchitis and as a stimulant to 
the mucous surfaces in catarrhal affections. It will be found in some of 
the prescription remedies recommended for diseases of the throat and 
lungs. Mixed with collodion it produces a very effective skin varnish. 

MECCA BALSAM 

Mecca balsam or balm of Gilead is a terebinthinate-like exudation 
from Balsamodendron gileadense syn. Commiphora opabalsamum, Bur- 
suracese, and has been employed in medicine for the same purposes gener- 
ally as Canada balsam and the turpentines. It contains about 10 per 
cent of volatile oil and is soluble completely in ether. It is not completely 
dissolved by alcohol and petroleum ether. The data regarding the action 
of other volatile solvents are discrepant, but this is probably due to the 
condition of the samples reported on. 

Dieterich examined fresh and old resinified meccas and obtained the 
following data: 

Fresh Old 

Acid value 39.84- 39.96 60.77-61.37 

Estervalue 101.1-101.39 81.90-82.66 

Sapon. value, cold 140 . 94-141 . 35 142 . 67-144 . 03 

He observed that when fresh the balsam had a very pale color, highly 
agreeable aromatic odor, and lower specific gravity than the old, the latter 
having a turpentine-like odor and was dark brown and viscid. 

COPAIBA BALSAM 

Several species of Copaiba and Hardwickia (Leguminosese) yield oleo- 
resinous exudations extensively used in diseases of the mucous membrane 
of the genito-urinary organs and in chronic skin diseases such as leprosy 
and psoriasis. The medicinal copaiba is limited officially to the genus 
Copaiba and the commercial oleo-resins are obtained from South America, 
the Brazilian tree, C. langsdorfii being one of the chief sources. C. 
copallifera of West Africa exudes an oleo-resin closely resembling the 
South American product, and Hardwickia manii of Africa and H. pimenta 
of India also furnish drugs which to all intents and purposes answer the 
description of copaiba balsam. 

Gurjun balsam, which resembles copaiba, and is often mixed with it, 
possesses medicinal properties similar to those of copaiba. It comes from 
several species of Dipterocarpus (Dipterocarpacese) growing in the East 
Indies. 



GUMS AND RESINS 491 

Copaiba is administered in capsules, pills, and tablets; it is combined 
principally with oleoresin cubeb, santal wood oil, olive oil, and methylene 
blue. Other medicinal agents sometimes added to the ordinary copaiba 
mixtures include turpentine, buchu, matico, Krameria, salol, pepsin, guaiac, 
ferric citrate, iron and anmionium citrate, and ferrous sulphate. Copaiba 
resin deprived of its volatile oil is occasionally used medicinally. 

There are several varieties of copaiba distinguished by names repre- 
sentative of the countries of their production or the ports of shipment. 
The chief commercial varieties are the Maracaibo, Maranham, and Para. 
The former are representative of the type of thick balsams and the latter 
of the thin. 

Copaiba consists of from 40-75 per cent of volatile oil and 60-25 per 
cent of resin. Caryophyllene has been detected in the volatile oil. The 
peculiar and almost characteristic odor of copaiba is due to the volatile 
oil, and this odor is generally observed in the breath of a patient to whom 
the drug has been administered. 

Copaiba balsam consists of amorphous resin acids, resenes, crystalline 
resin acids, and volatile oil. The volatile oil will run from 40-75 per cent. 
The crystalline resin acids have been studied. Para balsam contains para- 
copaivic acid, C20H32O3, melting 145-148°, soluble in ammonium carbon- 
ate solution; and homo-para-copaivic acid, CisE^sOs, melting 111-112° 
and insoluble in anunonium carbonate. Maracaibo balsam contains meta- 
copaivic acid, CnHieCb or C16H24O3, melting 89-90° C. Illurinic acid has 
been reported in Maracaibo balsam. It is one of the constituents also 
of African copaiba. 

Bitter principles are present in all varieties. The analysis of copaiba 
has been handicapped because of the uncertainty of the purity of the prod- 
uct under examination and many of the published reports are therefore 
unreliable. Adulteration has been practiced with gurjun balsam, olive 
and castor oils, storax, colophony, turpentine, sassafras oil, paraffin, etc., 
and often one variety of copaiba is mixed with another. 

The U. S. Pharmacopoeia specifies that the official oleoresin shall con- 
tain not less than 36 per cent resin, and shall have an acid value of not less 
than 28 nor more than 95. It should be soluble in an equal volume of 
petroleum ether, a further addition of the solvent producing a rlocculent 
precipitate. The volatile oil distilled from copaiba should not boil below 
250° and should have a rotation not less than —70 at 25° C. in a 100-mm. 
tube. 

The specific gravity of copaiba runs from .95-.97 in the case of Para 
and .98-99 in the case of Maracaibo, though old samples of the latter will 
run slightly over 1. Maracaibo oleoresin is completely soluble in ether, 
chloroform, petroleum ether, oil of turpentine, and carbon disulphide, and 
almost completely in 90 per cent alcohol and acetic ether. Para copaiba 



492 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

is not as completely soluble in petroleum ether and carbon bisulphide as 
the Maracaibo, but otherwise shows the same solubility. 

The examination of a sample of copaiba should include the determi- 
nation of the constants and reactions prescribed in the Pharmacopoeia, and 
in addition the saponification and ester values. In order to test the vola- 
tile oil, a complete separation of this ingredient should be effected by 
steam distillation, and the separated oil filtered. It would be useless to 
attempt to determine the boiling-point of the oil by distilling it from the 
oleoresin directly over a fllame. 

In order to determine the acid, saponification, and ester values, the 
procedure recommended by Dieterich will prove advantageous. 

Acid value, direct, 1 gram of the oleoresin is dissolved in 200 mils of 
96 per cent alcohol and titrated with N/2 alcoholic potash in presence of 
phenolphthalein. The volume of alkali consumed multiplied by 28.08 
gives the acid value. 

Saponification value, cold. One gram is placed in a stoppered 1-liter 
flask and treated with 20 mils N/2 alcoholic potash and 50 mils petroleum 
ether (sp. gr. 0.700). After standing for twenty-four hours at room tem- 
perature, the contents are diluted with 95 per cent alcohol and titrated 
back with N/2 sulphuric acid and phenolphthalein. The saponification 
value is found by multiplying the volume (mils) of combined KOH by 
28.08. 

The ester value is found by calculation. 

The results of the examination of a number of samples of authentic 
copaibas are tabulated below: 

K. Dieterich has reported an interesting research where he added 
known amounts of the well-known adulterants to authentic Maracaibo 
and Para oleoresins and determined the specific gravity, acid, saponifica- 
tion, and ester values. He concludes that the added adulterants modify 
the constants of the normal Maracaibo copaiba in the following 
manner : 

1. Gurjun balsam increases specific gravity, lowers acid value, and 
raises saponification and ester values. 

2. Olive oil reduces specific gravity and acid value, but considerably 
increases the ester and saponification values. 

3. Sassafras oil heightens specific gravity, lowers acid and saponi- 
fication values, leaving ester value almost unchanged. 

4. Oil of turpentine reduces specific gravity, acid value, and saponi- 
fication value, but considerably increases ester value. 

5. Venice turpentine increases specific gravity, acid and saponi- 
fication values, leaving ester value almost unchanged. 

6. Colophony greatly increases specific gravity and acid value. No 
definite conclusions deducible from ester and saponification values. 



GUMS AND RESINS 



493 



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494 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

7. Liquid paraffin reduces specific gravity and acid value, increases 
ester value, but leaves saponification value about normal. 

8. Castor oil reduces specific gravity and acid value, considerably 
increasing ester and saponification values, like olive oil. 

9. Resinified old balsam. The acid and saponification values and 
specific gravity are greatly increased, analogous to the influence of colo- 
phony. 

The effects of adulterants on normal Para balsam may be stated as 
follows : 

1. Gurjun balsam increases the specific gravity, saponification and 
ester values, and reduces acid values. 

2. Olive, castor, and other fatty oils lower the specific gravity and 
acid value, but considerably increase the saponification and ester values. 

3. Sassafras oil heightens the specific gravity, but depresses the acid 
and saponification values. 

4. Oil of turpentine lowers the specific gravity and acid value, but 
largely increases the ester value. 

5. Venice turpentine raises the specific gravity, acid, saponification, 
and ester values. 

6. Colophony raises the specific gravity, acid and saponification 
values. 

7. Liquid paraffin reduces the specific gravity, greatly lowers the 
acid value, and increases the ester value. 

Many color tests have been proposed for the detection of adulterants, 
but practically all have been discarded as unreliable. The U. S. Phar- 
macopoeia recognizes one reaction for the presence of Gurjun balsam to be 
applied on the volatile oil, 3-4 drops of the oil distilled from the balsam 
with steam are treated with 3 mils of glacial acetic acid and 1 drop of 
freshly prepared sodium nitrite solution (1-10) and underlaid with 2 mils 
of concentrated sulphuric acid. The acetic layer should not show a pink 
color. 

Deussen * claims that the optical rotation of the oil furnishes the most 
important information. The balsam is distilled with steam as completely 
as possible; the oil is separated from the distillate, dried with sodium 
sulphate, filtered and the rotation determined. 

Oil of Copaiba (Maracaibo or Para) 

The oil distilled from copaiba oleoresin is a, colorless, yellowish, or 
brownish liquid, with the characteristic odor of the drug, and a bitter, 
grating taste. It has a specific gravity 0.900-0.910; (a) D =—7 to 35°; 
boiling 250-275°; refractive index 1.4943-1.5026 (Evans). 
1 Arch. Pharm., 242 ; 1914, 590. 



GUMS AND RESINS 495 

It is not completely soluble in 90 per cent alcohol, but dissolves in an 
equal volume of absolute alcohol. 

Deussen states that the specific rotatory power of an oil from an 
unadulterated Maracaibo oleoresin calculated for a 10 cm. tube should 
be between -2.5-14°. 

The oil from Maranham balsam has sp. gr. 0.889-0.90; rotation = — 13° 
to -21°; refractive index 1.494-1.4992 (Evans). 

The sesquiterpene caryophyllene, C15H24, has been isolated from the 
oil and may be separated from the fraction distilling between 250-270° 
by treatment with glacial acetic acid and sulphuric acid and warming on 
the water-bath, which throws out the hydrate, C15H25OH, melting 94- 
96° C. The hydrate may be freed from the oily material by filtering and 
then crystallized from alcohol. 

A volatile oil has been reported from an African copaiba. This prod- 
uct had specific gravity .917-.918* rotation = +20° 42'. No caryophyllene 
was obtained. 

AFRICAN OR ILLURIN COPAIBA 

This balsam contains from 2-3 per cent of illurinic acid, C20H28O3, 
melting 128-129° C. This acid is crystalline and strongly laevorotatory 
(«)/>=— 54° 89'. The crystalline barium salt is characteristic and may 
be obtained when an ethereal solution of the acid is shaken with barium 
hydroxide solution. A few needles appear in a short time and then sud- 
denly the whole ether layer is covered with a network of fine needles. 

The volatile oil from African copaiba rotates the plane of polarized 
light to the right, thus differing radically from the oils of South American 
copaiba, which are lsevogyrate. 

According to the present rulings, the substitution of African copaiba 
for the official varieties constitutes an adulteration. 

GURJTJN BALSAM 

Gurjun balsam has a specific gravity of .955-.979, acid value 5.0-10.98 
saponification value 10-26.35, and ester value 1-15.37; most of these 
values being determined by K. Dieterich. By steam distillation up to 
70 per cent of oil are obtained. The odor and taste resemble copaiba. 
The color is greenish gray; with reflected light somewhat turbid and 
slightly fluorescent, with transmitted light, clear and reddish brown. 

The volatile oil is a yellow, somewhat viscous liquid, sp. gr. .915-. 930; 
(«)z>=-35° to 130°. It distills almost completely between 225°-256°. 
It is not completely soluble in 90 per cent alcohol. Its chief constituent 
is a sesquiterpene, C15H24, but its identity has not been determined. 

It is claimed that when taken internally, gurjun balsam imparts no 
unpleasant odor to the breath. 



496 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The chief concern of the analyst is in the testing of the commercial 
drug and with the data and directions set forth the examination should 
present no difficulties. 

The presence of copaiba in a medicine is usually apparent by the odor, 
though if the resin alone has been used the odor may be faint or even 
absent. The question then may be. to determine whether the oleoresin 
or the volatile oil has been used or whether copaiba or gurjun is the medica- 
ment in hand. Being a complex mixture itself, its complete separation 
from other ingredients of a compound medicine is practically impossible. 

If the product under examination contains no great amount of resin- 
ous matter and the proportional amount of volatile oil in the whole is 
large, it is quite probable that the oil and not the oleoresin has been 
employed. If the volatile oil contains caryophyllene and this sesquiterpene 
can be separated by means of its hydrate or some other derivative and its 
identity established, and if the absence of clove oil is established, and 
furthermore, if the volatile oil does not give the color reaction for gurjun, 
it is safe to assume that copaiba and not gurjun is present. 

Copaiba is incorporated into pills and tablets in the form of copaiba 
mass or solidified copaiba, which is obtained by mixing the oleoresin with 
magnesium or calcium oxide and water. This mass may contain 90 per 
cent or more of the oleoresin. In pills and tablets the copaiba mass will 
run from | grain up to 2 or 3 grains. In capsules the oleoresin may run 
from 3 to 10 minims. No satisfactory method for the determination of 
copaiba in medicines can be offered. An approximate estimation of the 
amount present can, however, be made with a fair degree of accuracy by 
one who has considerable experience with copaiba mixtures, but this is 
due more to the personal equation and cannot be set down in black and 
white. 

AMMONIACUM 

True or Persian. — Ammoniacum is the gum resin of Dorema ammoni- 
acum (Umbelliferse) which is a native of Persia, Northern India, and South- 
ern Siberia. 

It is used as an expectorant, stimulant, and antispasmodic in chronic 
catarrh, asthma, and bronchial affections, and is often combined with 
ipecac and squill in pills and tablets. It also has some reputation as an 
emmenagogue and diuretic. It is used externally for treating indolent 
ulcers and white swelling of joints, and is applied in plaster form as a 
rubefacient for chronic rheumatism. 

The natural gum-resin consists of 60-70 per cent of acid and neutral 
resin, soluble in ether, a considerable portion (12-30 per cent) of gum, 
volatile oil, free salicylic, acetic, and caproic acid, water and vegetable 
debris. The acid resin is a salicylic ammoresinotannol ester, and the 



GUMS AND RESINS 497 

isolated ammoresinotannol appears to be closely allied to galboresino- 
tannol. The gum is similar to acacia and yields on hydrolysis galactose, 
arabinose, mannose, and an acid. Oxidation with nitric acid yields mucic 
acid and galactose, but not saccharic acid. The volatile oil has n. 1.4747- 
1.4808, and give the color reaction with sodium hypobromite described 
below. This oil has a specific gravity .891 at 150° and melts principally 
between 250-290°. Its odor is similar to that of angelica. Umbellif- 
erone and sulphur are not present. 

Ammoniacum occurs in irregular, rounded tears, yellowish outside 
and whitish within; opaque, brittle when cold, but soft when warm. 
It also occurs in masses darker in color and less homogeneous. The odor 
is peculiar and the taste is sweetish, bitter, and somewhat acrid. The 
masses contain a large quantity of volatile oil and are greasy, while the 
tears are solid. The gum resin, owing to its composition, is partially 
soluble in alcohol and water. 

African ammoniacum is much darker in color and differs in taste and 
odor. It differs from Persian ammoniacum in proximate analysis and 
contains umbelliferone. 

Adulteration with galbanum and African ammoniacum has been prac- 
ticed. Other resinous and vegetable material are also used to sophisti- 
cate the pure product. 

An alcoholic solution of ammoniacum gives a violet color with sodium 
hypochlorite and hypobromite. This test being of value in establishing 
the identity of ammoniacum in medicines and when mixed with other 
gum-resins. 

Dieterich records the following constants for commercial ammoniacum : 

Ash up to 10 per cent. 

Loss at 100° C, 2.15-12 per cent. 

Volatile acid value, 100-200. 

Acid value ind., 90-105. 

Resin value, 99.4-155.4. 

Gum value, 7.0-46.2. . 

Total saponification value, 145.6-162.4. 

A good ammoniacum shows a high volatile acid value and a low gum 
value. 

African Ammoniacum tested by Dieterich showed the following figures: 

Acid value ind., 47.59-92.21. 

Resin value, 103.89-104.59. 

Total saponification value, 105.3-108.1. 

In general the values are lower than those given by Persian ammoni- 
acum. 

Dieterich's Methods for Assaying Ammoniacum. — The drug should 
be thoroughly chilled and ground in a cold mortar. 



498 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Volatile Acid Value. — 0.5 gram is mixed with a little water in a flask, 
through which a current of hot steam is passed , the flask being heated in 
a sand-bath. The receiver contains 40 mils of N/2 KOH, into which dips 
the tube coming from the condenser. Five hundred mils are distilled and 
the excess alkali titrated back in presence of phenolphthalein. The num- 
ber of mils of KOH combined, multiplied by 28.08 gives the volatile 
acid value referring to 0.5 gram. 

Acid Value Ind. — One gram is boiled under a reflux with 50 grams 
water for fifteen minutes, followed by 100 grams alcohol for an equal 
time. After cooling the weight is made up to 150 grams, filtered and 
75 grams of filtrate (0.5 gram of substance) are treated with 10 mils of 
N/2 alcoholic KOH, allowed to stand exactly five minutes and titrated 
back with N/2 sulphuric acid and phenolphthalein. The number of mils 
of combined KOH multiplied by 28.08 and referred to 1 gram of the sub- 
stance gives the acid value. 

Resin Value and Gum Value. — Two samples of 1 gram each are used. 
Each sample is treated in a 1000-mil stoppered flask with 50 mils petroleum 
ether (sp. gr. .700) followed by 25 mils N/2 alcoholic KOH, which is 
allowed to act in the cold for twenty-four hours, agitation being frequent. 
One sample is then treated with 500 mils of water and titrated back with 
N/2 sulphuric acid and phenolphthalein — this gives the resin value. The 
second sample is treated with 25 mils of N/2 aqueous KOH and 75 mils 
water and left, with frequent agitation twenty-four hours, then diluted 
with 500 mils of water and titrated with N/2 sulphuric acid, the result 
being the total saponification value. The respective quantities (mils) of 
KOH consumed multiplied by 28.08 gives the corresponding values. 

The gum value is found by subtracting the resin value from the total 
saponification value. 

Test for Galbanum. — Five grams are boiled with 15 mils strong hydro- 
chloric acid for fifteen minutes, filtered until clear filtrate is obtained and 
then supersaturated with ammonia. If umbelliferone is present the liquid 
will show the characteristic blue fluorescence in reflected light. 

The actual gum present can be determined approximately by dissolving 
1-2 grams of the sample in sufficient 60 per cent chloral hydrate solution 
and pouring into 100-150 mils of 95 per cent alcohol. The precipitated 
gum is collected on a tared Gooch, washed with alcohol and weighed. 

GALBANUM 

Galbanum is the gum-resin of Peucedanum galbanifluum P. rubricaule 
and allied species of Umbelliferse, indigenous to Persia 

It is employed medicinally as a stimulant, carminative, and expector- 
ant, chiefly in chronic affections of the mucous membranes, bronchial, 
uterine, and vaginal catarrh, and is offered in pill form combined witfi 






GUMS AND RESINS 499 

myrrh and asafetida. Externally it is used as an irritant and mild stimu- 
lant in plasters. 

Galbanum consists of from 10-20 per cent volatile oil, 50-67 per cent 
resin, 15-20 per cent gum, mineral matter and vegetable debris. The 
resin is soluble in ether and alkalies, and contains about .25 per cent free 
umbelliferone, galboresinotannol, and about 20 per cent umbelliferone 
combined with the resinotannol. The volatile oil has an aromatic and 
not unpleasant odor, yellowish in color, sp. gr. .910-.940 (.908-.955 Harri- 
son and Self) and is reported as dextrogyrate up to +20° and laevo up to 
— 10°. n= 1.4863-1.4869. It is reported as containing d-pinene and 
cadinene, the latter being identified by the preparation of its hydrochloride, 
melting 117-118°. On dry distillation galbanum yields a blue oil having 
the odor of chamomile. On fusion the resin yields resorcin and an acid. 

Galbanum occurs in agglomerated tears or masses, grayish yellow or 
greenish, with a wavy luster. The odor is balsamic and the flavor bitter, 
acrid, and burning. It is partially soluble in water, alcohol, and ether. 
When boiled with hydrochloric acid, filtered, and supersaturated with 
ammonia, a blue color, due to umbelliferone, appears. 

Galbanum is often adulterated with ammoniacum, turpentine, fatty 
oils, sand, exhausted galbanum, and vegetable material. 

Dieterich's researches on galbanum showed the following constants: 

Volatile acid value, 73.5-114. 

Acid value ind., 21.24-63.45. 

Resin value, 107.5-122.5. 

Total saponification value, 116.2-135.8. 

Gum value, 8.4-16.1. 

Ash, 8.4-16.1 per cent. 

Loss at 100°, .35-31.5 per cent. 

Galbanum should be assayed by the methods described for Ajnmoni- 
acum. The quantity of the gum is determined by the precipitation of a 
chloral hydrate solution with alcohol. 

Dieterich concludes that adulteration with ammoniacum decreases 
the volatile acid value, while asafetida has the reverse effect. Asafetida 
is readily detected by the characteristic odor during distillation. The 
indirect acid value is raised by ammoniacum but is reduced by asafetida. 
The presence of ammoniacum is indicated by the color reactions given 
with sodium hypochlorite and sodium hypobromite. 

GAMBOGE 

Gamboge is a yellow gum resin from Garcinia morella (Clusiacese) 
indigenous to Siam and Ceylon. 

It is a valuable cathartic and is often found in combination with other 
drugs in remedies for obstinate constipation, intestinal torpidity and 



500 GLUCOS1DES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

hepatic troubles. The U. S. P. compound cathartic pills contain gam- 
boge, jalap, colocynth comp. and calomel; other pill formulas consist of 
gamboge with aloes, Podophyllum, Capsicum and croton oil; with colo- 
cynth comp., jalap, ginger, rhubarb, and calomel; with jalap, Leptandra, 
aloin, Podophyllum, Capsicum, Hyoscyamus, peppermint; with aloes, 
colocynth, soap, and anise; with Veratrum viride, croton oil, aloes, jalap 
Podophyllum, Capsicum, and Leptandra. 

Gamboge consists of resin, gambogic acid, gum, wax, and vegetable 
debris. The resinous material amounts to 75-82 per cent, the gum about 
16 per cent. No volatile oil is present. It occurs in the trade in the 
form of pipes, cakes, lumps, and powder. The color is reddish yellow 
and the dry lumps have a chonchoidal lustrous fracture. It floats on 
carbon bisulphide at a temperature of 20° C. but sinks at higher temper- 
atures. It is soluble in alkalies, and 60 per cent chloral hydrate, forms 
a yellow emulsion with water, partly soluble in alcohol, ether, and other 
volatile solvents. 

Gamboge is often adulterated with colophony and in the powdered 
form was formerly almost never found free from admixture with starch. 
Other impurities consist of sand, dirt, dextrin, turmeric, and Taylor 
reports an instance of dangerous sophistication with lead chromate. 
Starch is almost always present in small quantity in powdered gamboge 
which is otherwise pure and the reason for the presence of minute quan- 
tities which can hardly be considered as intentional adulteration is not 
apparent. The mineral matter (ash) of pure gamboge should not exceed 
1 per cent. 

Starch may be detected by boiling some of the powdered drug with 
water, cooling, and adding iodin. A faint-green color will often appear 
at this juncture, but any color darker than this indicates adulteration. 
Eberhardt recommends boiling 1 gram of the powdered material with 5 
per cent potassium hydroxide solution, neutralizing with acid, filtering, 
and testing the nitrate with iodin. There are certain advantages to the 
last procedure as the blue color of any starch iodide formed is not altered 
by the yellow pigment of the gum-resin; 2 per cent or over of starch will 
yield a blue precipitate. 

Good gamboge should contain not more than 25 per cent of material 
insoluble in 95 per cent alcohol. 

Taylor 1 determines both the alcohol-soluble portion of the gum resin 
and the acid value with one sample. Two grams of the powdered sample 
are digested with heat under a reflux condenser with exactly 150 mils 
95 per cent alcohol for not less than fifteen minutes, the solution cooled 
and 75 mils (representing 1 gram of the resin) filtered off through a dry 
tared filter. This 75 mils is used for titration of the acid value, which is 
1 J. Ind. and Eng. Chem.. 1910, II, 208. 



all pure gamboges 



GUMS AND RESINS 501 

made direct on this solution, and the nitration is continued so that the 
insoluble residue may be finally collected in the filter and weighed. The 
acid value titration gives results agreeing with those obtained by 
Dieterich's method. 

The acid value runs from 80-96 and this value varies in direct propor- 
tion to the alcohol solubility with few exceptions. In other words* a 
high alcohol solubility usually accompanies a high acid value. Some of 
Taylor's figures illustrative of this relationship are appended. 

Acid Value Alcohol Solubility 

95.8 84.0 

91.6 79.05 

88.6 82.0 

85.8 77.4 

85.8 77.0 

81.6 74.9 
80.2 76.15 
80 . 5 52 . 95 starch adulterant 

67 . 7 57 . 6 colophony adulterant 
67 . 7 613 colophony adulterant 

Dieterich's method for determining the resin value and total saponi- 
fication value: 

Two 1-gram samples of finely triturated gamboge are each covered 
with 25 mils N/2 alcoholic KOH and allowed to stand tightly stoppered 
for twenty-four hours. One sample is then diluted with water and 
titrated, the volume of the KOH consumed multiplied by 28.08 giving 
the resin value. The second sample is then treated with 25 mils N/2 
aqueous KOH, allowed to stand twenty-four hours longer and titrated, 
the result giving the saponification value. The gum value is obtained by 
difference. 

Dieterich found the resin value to run from 105-116.2; the total 
saponification value from 121.8-138.6, the gum value from 14-22.4 

The percentage of gum may be determined by Mauch's method. The 
sample is dissolved in 5 parts of 60 per cent aqueous chloral hydrate, pre- 
cipitated by alcohol, and the gum collected on a tared Gooch, washed with 
alcohol and weighed. 

LACTUCARIUM 

Lactucarium is the dried milky juice of Lactuca virosa (Compositse) 
and other species of Lactuca. It is obtained by cutting off the tops of 
the stems and when the latex which exudes is partially hardened, it is 
collected and dried in hemispherical earthen cups until it can be cut into 
pieces and which are usually four in number, these being further dried. 

It occurs in commerce in irregular, angular pieces or quadrangular 
sectors, one surface of which is convex, externally dull reddish or grayish 



502 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

brown; fracture tough, waxy, internally light brown or yellowish, some- 
what porous, odor distinct and opium-like, taste bitter. 

It is partly soluble in alcohol, ether, chloroform, and water. 

Three bitter principles are reported as occurring in lactucarium, lac- 
tucin, which occurs in white rhombic prisms, sparingly soluble in water; 
lactucopicrin, a brown, amorphous, very bitter principle which is readily 
soluble in water and alcohol; and lactucic acid, a yellow, very bitter 
substance crystallizing with difficulty and colored red by alkalies. It 
contains also about 50 per cent of a colorless, odorless, and tasteless crys- 
talline substance, lactucerin (lactucon) ; a- and /3-lactucerol in the form 
of acetates, volatile oil, mannitol, organic acids, citric, malic, and oxalic. 

The principal use of lactucarium is in a certain class of anodyne syrups 
recommended for infants. It may be combined with opium in these 
remedies. It also enters into the composition of some syphilitic pills 
with mercurous iodide, opium, and Conium. 

The commercial varieties include German and English lactucarium 
and Lactucarium Gallicum from L. sativa, the " Thridax " of ancient days. 

German lactucarium forms tough, homogeneous, yellow-brown masses, 
somewhat waxy in fracture and hygroscopic. The English drug consists 
of irregular, larger, and smaller granules, more or less obtuse angled, dull, 
friable, dark brown in color and non-hygroscopic. Gallicum is a blackish- 
brown fatty extract. 

Lactucarium is adulterated with farinaceous material, vegetable 
extracts, and colophony. 

The important constants of lactucarium are determined by Dieterich 
as follows: 

Two 1-gram samples of the powdered drug in stoppered liter flasks are 
covered with 50 mils petroleum ether (sp. gr. .700) followed by 25 mils 
N/2 alcoholic KOH, and allowed to stand for twenty-four hours with 
frequent shaking. One sample is then diluted with 500 mils of water and 
titrated back with N/2 sulphuric acid, the results giving the resin value. 
The second sample is further treated with 25 mils of N/2 aqueous KOH and 
75 mils water and allowed to act with occasional agitation twenty-four 
hours longer. It is then diluted with 500 mils of water and titrated back 
with N/2 sulphuric acid, the results giving the total saponification value. 
The gum value is determined by difference. 

For German lactucarium in mass Dieterich found resin value 154- 
156.8; total saponification value 166.6-169.4; gum value 12.6. High 
resin and saponification values indicate adulteration with colophony 
which should be tested for by the Storch-Morawski reaction. 

The results Dieterich obtained on the English drug indicated irregular 
composition; resin value from 50.4-225.4; saponification value 75.6- 
238; gum value 7-26.6. It is probable that the excessively high data 



GUMS AND RESINS 503 

for resin and saponification values were obtained with sophisticated 
products. 

MYRRH AND ITS ALLIED GUM RESINS. (HERABOL MYRRH) 

Myrrh is the dried emulsion-like juice which exudes from several 
species of Commiphora and Balsamodendron (Burseracese), native in the 
coast districts of the Red Sea such as the Somali coast of East Africa, in 
Arabia, and probably Persia. From the interior of the Somali lands there 
comes a variety of myrrh (bisabol) which has been ascribed to Baisamea 
erythrea, belonging to the same family, and which has been considered 
identical with commercial opopanax. The latter drug occurs in two 
varieties, the burseraceous and umbelliferous, the former being found 
in the trade, and its source has been ascribed to the species Balsamoden- 
dron kafal. As a matter of fact the botanical origin of these gum resins 
has not been traced with entire satisfaction and any statements regard- 
ing the species yielding the burseraceous gum-resins must be taken with 
reserve. 

Herabol myrrh is the usual commercial grade. It has a wide and 
varied use in medicine, for besides being a valuable constituent of mouth 
washes, tooth powders, and applications for spongy gums and sore throat, 
it is a stimulating tonic with apparently some influence on the lungs and 
uterus and is found in female pills, liquid aloes mixture, expectorants, etc. 
Myrrh is combined with aloes and licorice in fluid compounds of aloes, 
and also with Capsicum. It also accompanies aloes in many different 
pill formulas. Female pills contain myrrh, aloes, ferrous sulphate, helle- 
bore, ginger, soap, and Canella. Other formulas containing myrrh include 
asafetida and galbanum; rhubarb, aloes, soap, and peppermint; aloes 
and mercury mass; aloes, scammony, croton oil, and caraway. Warburg 
tincture contains myrrh. Astringent mouth washes contain myrrh com- 
bined with glycerin and mild antiseptics and aromatics. Tooth powders 
often contain myrrh. Griffith's mixture, the compound iron mixture, 
consists of myrrh, ferrous sulphate, sugar, potassium carbonate, and 
flavors. The volatile oil of myrrh is employed as a remedy for bronchitis. 
Plasters contain myrrh, camphor, Peru balsam, and lead oleate. 

Herabol myrrh occurs in the form of masses and granules, yellowish 
red in color, with a greasy, lustrous, fine-grained fracture. It has a strong 
and characteristic odor and a bitter acrid taste. If forms a milky emul- 
sion with water and alcohol dissolves the resinous portion. This drug 
is the so-called " male myrrh." It consists of 50-75 per cent of gum; 
2.5-8 per cent of volatile oil, 20 per cent or more of resin. The presence 
of a bitter principle has been reported. The resin is a complex mixture 
containing neutral resin and resinous acids. The volatile oil has sp. gr. 
.988-1.007; (a) D =— 67° to —90°, and its solution in petroleum ether is 



504 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 



colored red by bromine vapors, a test which distinguishes this variety of 
myrrh from Bisabol myrrh and bdellium. The ash should not exceed 8 
per cent. 

Myrrh is adulterated with Bisabol myrrh, bdellium, gum arabic, and 
extracted myrrh resin. 

If Herabol myrrh is treated with petroleum ether (1-15), and six drops 
of the clear extract are mixed with 3 mils of glacial acetic acid and floated 
on the surface of 3 mils of concentrated sulphuric acid, the acetic layer 
develops a very pale rose color which does not increase in strength, and 
the surface of contact between the two layers shows at first a green color 
which turns brown with a green fluorescence on standing. With Bisabol 
myrrh a rose red zone immediately forms at the surface of contact and the 
coloration soon extends throughout the entire layer of acetic acid and 
remains persistent. 

Dieterich gives the following methods for determining the constants 
of myrrh: 

Acid Value. — One gram of the finely powdered nryrrh is treated with 
30 mils of distilled water and warmed for fifteen minutes under a reflux, 
50 mils of 95 per cent alcohol are added and the boiling repeated for fifteen 
minutes. After cooling the liquid is titrated with N/2 alcoholic KOH 
and the volume of alkali consumed multiplied by 28.08 gives the acid value. 

Saponification Value. — One gram of the sample is treated with 
30 mils of water, allowed to stand one-half hour, treated with 25 mils 
N/2 alcoholic KOH and boiled for one-half hour under a reflux on the 
steam-bath. After cooling and diluting with alcohol it is titrated back 
with N/2 sulphuric acid, the volume of alkali consumed multiplied by 
28.08 gives the saponification value. 

Ester Value. — This is found by difference. 

Alcohol Soluble. — Determined by extracting the sample with 95 per 
cent alcohol in a thimble in a Knorr or Soxhlet apparatus and weighing 
the undissolved portion. 

Dieterich reports the following values for myrrh and the allied gum- 



resms. 





Acid Value 


Ester Value 


Saponification 

Value 


Solubility 
in Alcohol, 
Per Cent 


Herabol myrrh 


25.48 


204.12 


229 . 60 


20 


Bisabol myrrh 


20.06 


125.54 


145.60 


50 


African bdellium .... 


9.73-20.8 


70-96 


82-111 




Indian bdellium 


35.6-37.19 


46.75-48.46 


82.44-85.65 




Burseraceous 










opopanax 


10.46-30.92 


81.94-97.24 


96.20-152.82 




Umbelliferous 










opopanax 


32.43-58.57 


105.46-142.6 


137.S9-199.07 





GUMS AND RESINS 505 

The percentage of gum in myrrh is determined by Mauch's method. 
One to two grams of the sample are dissolved in 10-15 grams of 60 per cent 
aqueous chloral hydrate and precipitated with 100 grams 95 per cent 
alcohol. The precipitate is collected on a tared Gooch, washed with alco- 
hol, and weighed. 

Bisabol myrrh contains a much smaller percentage of gum and a larger 
quantity of resin than Herabol myrrh. It contains a bitter principle, 
water, volatile oil, and vegetable debris. The resin contains free acids, 
a resene, and a neutral substance. This drug is known as " female myrrh." 

BDELLIUM 

African bdellium is probably derived from Commiphora africana, and 
East Indian bdellium from Balsamodendron indicum (Burseracese) . The 
African drug is in reddish oval or round lumps about J inch across, which 
have a greasy luster, and become soft and plastic when warmed. East 
Indian bdellium is in the form of shapeless agglomerated lumps about one 
inch in diameter, externally rough, uneven, dull, of a dark-brown color, 
a lustrous fracture, a sharp, bitter flavor and an odor resembling Bisabol 
myrrh. Bdellium furnishes a white emulsion with water like myrrh. It 
does not give the characteristic color reactions of myrrh with bromin 
vapor and its analytical constants are different. Our interest in the drug 
is chiefly on account of its being used as an adulterant of myrrh, and the 
methods of examination are precisely the same as detailed under that drug. 

Indian bdellium is employed in the East as a remedy for leprosy, 
syphilis, and rheumatism. 

OPOPANAX 

There are two distinct varieties of this gum-resin, one derived prob- 
ably from Balsamodendron kafal (Burseracese) of Persia and the other 
from Cheronium opopanax (Umbelliferse) of Southern Europe. 

The Burseraceous gum-resin consists of about 19 per cent of resin, 
gum, and vegetable debris up to 70 per cent, volatile oil 6-10 per cent, 
and moisture. The resin consists of a-panaxresene (C32H54O4); /3-pan- 
axresene (C32H52O5) ; panaxresinotannol (C34H50O8) ; an alcohol, chironal 
(C28H48O), and bitter principle. The oil has a greenish color and a 
pleasant balsamic odor. It resinifies readily on exposure to air, specific 
gravity 0.870-0.905; (a) D — 10 —12°. With bisulphite solution a brownish 
mass separates from the oil, which on sublimation yields white needles 
melting 134-134°, to which the name oponal (C20H10O7) has been given. 

This variety of opopanax is commonly designated as myrrh in the 
East and according to Holmes may probably be the myrrh of the Scrip- 
tures. Its odor is peculiar, resembling Sumbul and Bisabol myrrh. It 



506 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

occurs in large, brown yellow lumps with paler gummy granules and smaller 
white lumps. 

The chemical constants have been recorded under myrrh and may be 
determined by the same methods. 

Umbelliferous opopanax has a strong disagreeable odor and balsamic 
taste. An analysis showed 51.8 per cent ether-soluble resin (ferulic acid 
ester of oporesinotannol) ; 19 per cent ether-insoluble resin; 33.8 per cent 
gum; 8.3 per cent volatile oil, small quantities of ferulic acid, and vege- 
table residues. It occurs in greasy masses or brownish yellow lumps. 

ASAFETIDA 

This gum resin is a product of several species of Ferula (Umbellif- 
erse) the ninth revision of the U. S. P. designating F. asafetida and F. 
fetida as the chief sources. J. Small, who has examined the botanical 
sources of the fetid gum resins, assigns the white asafetida to F. rubri- 
caulis and the red variety to F. fetida. 

Asafetida is a component of sedative mixtures and remedies for whoop- 
ing cough, chorea, chronic bronchitis, hysterical affections, convulsions, 
flatulent constipation, asthma, and catarrh. It is sometimes dispensed 
in liquid form, but more often in pills or tablets. Sedative mixtures 
will consist of asafetida with sumbul, valerian, ferrous sulphate, and 
arsenous acid. It will be found combined with aloes and soap; with 
opium and ammonium carbonate; with Nux Vomica; with reduced iron 
and rhubarb; and with myrrh and galbanum. Asafetida is very exten- 
sively employed in veterinary practice especially in remedies for " heaves." 

At the time the Food and Drugs Act went into operation probably 
there was no imported drug which was so flagrantly adulterated as asafetida. 
The Pharmacopoeia had prescribed a standard for the drug but no atten- 
tion w T as paid to the requirements except by a few progressive manufactur- 
ing pharmacists. In general the importer paid little attention to the 
quality of the drug. The change in conditions after January 1, 1907, 
caused a storm of protest from the importers of asafetida, anl it was 
some time before the authorities could convince them that the standards 
of the Pharmacopoeia were reasonable, and were based on the examination 
of specimens of known purity. At that time the asafetida was adulter- 
ated with sand, gravel, and broken lumps of mineral matter, and the 
ash frequently ran over 50 per cent. Other gums and gum resins, gal- 
banum, African ammoniacum, rosin, and turpentine were also used, and 
after the more easily detectable mineral matter ceased to be a source of 
trouble, the sophistication with other resinous material persisted and 
still does. 

A peculiar gum resin of uncertain origin, known to the trade as pepper 



GUMS AND RESINS 507 

asafetida, should not be mistaken for the official drug. Its odor is similar 
when cold, but on heating a pungent, peppery odor develops which is 
not characteristic of true asafetida. The lead number is low, 82. 

Asafetida consists of about 62 per cent of the ferulic acid ester of 
asaresinotannol, small amounts of free ferulic acid and asaresinotannol, 
about 25 per cent of gum, 3-17 per cent of volatile oil, a trace of vanillin, 
moisture, and mineral matter, the latter amounting to not over 10 per 
cent in a good crude drug. 

The steam-distilled oil possesses the disagreeable, alliaceous odor of 
the drug. It has specific gravity .975-.990; n 1.4942-1.5250; (a) D -9° 15' 
(Gildermeister and Hoffman), -35° 55' to +9° 39' (Harrison and Self). 
It contains two terpenes, one identical with pinene, and several sulphur 
compounds which * were fractioned by Semmler, and found to be a disul- 
phide C7H14S2, boning 83-84° at 9 mm.; sp. gr. 0.9721 at 15°; (o:)z>-12 
30', comprising about 45 per cent of the crude oil. 

A disulphide, CiiH 20 S 2 , sp. gr. 1.0121; boiling 126-170° at 9 mm.; 
{a) D — 18° 70', comprising 20 per cent of the oil and being the cause of 
the repulsive odor of the drug. 

A substance (Ci Hi 6 O)ri, sp. gr. .9639 at 22°; boiling 133-145° at 
9 mm.; {a) D — 16° present to the amount of 20 per cent and yielding cadi- 
nene, C15H24, on treatment with sodium. 

A compound, C 8 Hi6S2, boiling 92-96° under 9 mm. 
A disulphide, Ci Hi 8 S 2 , boiling 112-116°. 

Harrison and Self consider this oil, and especially its sulphur content, 
an important factor in the valuation of the drug and their method of 
procedure is subsequently described. 

Pure asafetida will show acid value 65-80, ester value 80-130, saponi- 
fication value 120-185, lead number 200 up, ash 1-10 per cent. 

Analysis of Asafetida. — It is important to obtain a fair average sample 
of a lot of asafetida and poor sampling is usually the cause of divergent 
results in cases of contest. Several drawings should be made from a 
package and these thoroughly mixed and if possible run through a sausage 
grinder to ensure homogeneity. 

Alcohol Soluble. — Introduce about 10 grams of asafetida into a tared, 
250 Erlenmeyer flask, determine the exact weight of the drug, add 100 
mils of alcohol, and having connected the flask with an upright condenser, 
boil the mixture in the flask during one hour or until the drug is completely 
disintegrated. Then transfer the contents of the flask to two counter- 
poised, plainly folded filters, one within the other, so that the triple fold 
of the inner filter is laid against the single side of the outer, and wash the 
flask and filter with consecutive, small portions of boiling alcohol until 
the washings no longer produce a cloudiness when dropped into water. 
Collect and reserve the mixed alcoholic solutions, for the qualitative tests 



508 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

given below. Dry the niters and flask to a constant weight at a temper- 
ature of about 115° C. Now determine the weight of the residue on the 
filter and in the flask and calculate its percentage from the amount of 
asafetida originally taken. This percentage of alcohol-insoluble material, 
when subtracted from 100, gives the percentage of alcohol-soluble con- 
stituents contained in the asafetida. 

Acid Value. (Dieterich). — One gram is treated with 10 mils each of 
N/2 alcoholic and aqueous KOII, and left to stand in a stoppered liter 
flask for twenty-four hours at room temperature. After dilution with 
500 mils of water, the whole is titrated back with N/2 sulphuric acid. 
The volume of KOH consumed multiplied by 28.08 gives the acid value. 

Saponification Value. (Dieterich) . — One gram is treated with 25 mils 
N/2 alcoholic KOH and boiled for one hour under a reflux. At the end 
of that time 200 mils of alcohol are added and when cold the whole is 
titrated back with N/2 sulphuric acid. The volume of KOH consumed 
multiplied by 28.08 gives the saponification value. 

The ester value is determined by difference. 

Gum Assay. — One to two grams of the sample are dissolved in 10-15 
grams of 60 per cent chloral hydrate filtered from mineral matter, the 
filter washed with the reagent and the gum precipitated by pouring the 
mixture into 10 parts of 95 per cent alcohol. The precipitate is collected 
on a tared Gooch, washed with alcohol, dried and weighed. 

Ash Determination. Mauch's Method. — The sample is treated with 
ten to fifteen times its own weight of 60 per cent chloral hydrate solution, 
filtered onto an ashless filter, washed with chloral hydrate solution followed 
by alcohol, dried and ignited. 

Determination of Sulphur in Asafetida Oil. — Harrison and Self 1 
determine the amount of sulphur in the volatile oil and refer the figure 
thus obtained to the amount of real gum resin in the drug. Therefore, 
account must be taken of the ash content. They claim that the amount 
of sulphur should not be below 1.5 per cent on the gum resin basis and 
may run to 4.04 per cent. 

A weighed amount of the drug is subjected to steam distillation and the 
oil collected. The oil is separated and dried, 0.5 gram is weighed into 
a flask of 150 mils capacity fitted with a ground-in condenser; 5 mils of 
water are added, followed by 5 mils of nitric acid, sp. gr. 1.42. The 
flask is gently warmed to start the reaction, 3 grams of potassium bromide 
are then added, the whole boiled for ten minutes, cooled and treated with 
5 grams of sodium hydroxide dissolved in a little water. The contents 
of the flask are evaporated to dryness and ignited in a platinum crucible. 
After dissolving in water, the nitric and nitrous acids are boiled off and 
the sulphur determined by precipitation with barium chloride in presence 

1 Pharm. J., 1912, 88, 205. 



GUMS AND RESINS 509 

of hydrochloric acid. A blank determination with materials used must 
also be made. 

If there is a large percentage of volatile oil and a small percentage of 
sulphur the presence of terpenes is indicated. Admixture of galbanum, 
olibanum, and ammoniacum lower the percentage of sulphur in the gum 
resin as these drugs contain no sulphur in the oil. Volatile oil of ammoni- 
acum has n. 1.4747-1.4808, and as an adulterant would lower the oil con- 
tent. Galbanum has n. 1.4863-1.4869, 1.4840 (Sechler and Bechu), elemi 
has n. 1.4869. Both galbanum and elemi would lower the sp. gr. of oil of 
asafetida and increase the dextro-rotation, therefore decreasing the laevo- 
rotation. Galbanum contains umbelliferone, which can be detected by 
the blue fluorescence produced by alcoholic ammonia. Asafetida yields 
the blue fluorescence after boiling with hydrochloric acid, but olibanum 
and ammoniacum do not. 

LEAD NUMBER. (E. C. MERRILL) 

This method was proposed by H. A. Seil and was developed by Merrill 
and reported in the Journal of the A. 0. A. C, Vol. II, No. 1, page 83. 

Use a sample (about 20 grams) sufficient to furnish between 5 and 10 
grams of the ether purified resin. Determine the alcohol insoluble material 
in the usual manner. Transfer the first 2 filtrates, representing the major 
part of the sample, to a casserole or a flat-bottomed porcelain dish, and 
evaporate the alcohol on the steam-bath. Treat the resinous mass with 
ether (sometimes it is necessary to warm gently to facilitate solution of 
the resin). Filter the ethereal solution into a separatory funnel and wash 
with water until the aqueous layer separates without any milkiness. (If 
the ether solutions persist in remaining turbid, more ether may be added, 
or it may become necessary to dry the ether solution by shaking with 
sodium chloride in the separatory funnel after as much as possible of the 
aqueous solution has been removed.) Then filter the ethereal solution 
through a folded filter paper, moistened with ether, into a flask or beaker, 
and evaporate the solvent on the steam-bath. 

Determination. — (The residual ether purified resin from the above 
preparation is now in a state where it can usually be broken up when 
cold, and powdered.) 

Into a small tared beaker (about 75-mils capacity) weigh roughly 
about 1.1-1.2 grams of the resin prepared above and dry for five hours 
in the air-bath at 110° C. Place in a desiccator, cool, and weigh. (The 
weight noted is to be used in subsequent calculations.) Dissolve in 20 
mils of 95 per cent alcohol, boil gently until the resin is in solution, trans- 
fer to a 100-mil graduated flask, wash the beaker with hot 95 per cent 
alcohol, care being taken that the final volume does not exceed 70 mils. 



510 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

Add 25 mils of the alcoholic lead acetate, agitate and allow to stand 
overnight. Make up to the mark with 95 per cent alcohol, shake well, 
allow to stand a few minutes, and then filter through a fluted paper and 
pipette an aliquot of 25 mils from the filtrate into a beaker. Add 10 mils 
of water and evaporate to 10 mils. Add 5 mils of 10 per cent sulphuric 
acid and then 100 mils of alcohol, stirring vigorously to dissolve any 
separated resin, and heat if necessary. Allow to stand for an hour, then 
filter the lead sulphate on a tared Gooch, wash with alcohol and finally 
with ether, dry at 100° C. to a constant weight and weigh. 

Run a blank on the alcoholic lead acetate solution, and calculate the 
amount of metallic lead absorbed by 1 gram of the dried resin. The 
mg. of lead per gram of sample represent the lead number. The factor 
for the conversion of lead sulphate to metallic lead equals 0.6830. x 

The lead numbers of a number of authentic resins and gum resins 
determined by Merrill showed asafetida 222, galbanum 4, ammoniacum 
75, olibanum none, guaiac 171, myrrh 7, colophony 142, bdellium 55, 
sandarac 251, mastic 34, gamboge 9. dragon's blood, none, euphorbium 34, 
pepper asafetida 82. 

Qualitative Test for Colophony (Merrill). — For this test Merrill 
recommends using about 40 mils of the alcoholic solution obtained in 
determining the alcohol-soluble matter. Transfer to a separatory funnel, 
add 30 mils petroleum ether, mix, add 50 mils of water and shake for 
thirty seconds. After separating, discard the aqueous milky layer. Wash 
the petroleum ether layer with water until the wash water and petroleum 
ether are both clear. Add 30 mils of 0.5 per cent copper acetate solution 
and shake well. No green color should appear in the petroleum ether. 
The appearance of a green color indicates the presence of foreign resins. 

SAGAPENUM 

This gum resin is derived from a botanical source not yet satisfactorily 
identified but belonging to the Umbelliferse. It contains a volatile oil 
containing sulphur compounds, and its odor recalls both asafetida and 
galbanum. It contains a considerable portion of resins soluble in ether 
which has been found to consist of free umbelliferone and umbeiliferone- 
sagaresinotannol ester. Its ethereal solution gives a red-violet color with 
hydrochloric acid. Like galbanum it gives the umbelliferone reaction. 

1 For the preparation of alcoholic lead acetate dissolve 5 grams of normal lead ace- 
tate in 20 mils of water and add 80 mils of 95 per cent alcohol. A turbidity generally 
results, due to the precipitation of lead carbonate caused by carbon dioxide in the 
alcohol. Allow the solution to stand overnight. The clear, supernatant liquid can then 
be used without filtering for the determination of the lead number. 

The blank on 25 mils of alcoholic lead acetate solution should be equivalent to at 
least 1 gram, calculated as PbS0 4 . 



GUMS AND RESINS 511 

Its assay may be conducted by the procedure given under Myrrh and 
Dieterich has obtained the following values: 
Acid value, 13.96-14.81. 
Ester value, 31.29-39.37. 
Saponification value, 45.25-54.18. 

RUBBER AND CHICLE 

A detailed consideration of the chemistry of rubber and its uses is not 
within the scope of this work, but reference will be made to its composition 
and general characteristics for it will be encountered in testing plasters 
and chewing gums where it often functionates as a basic component. 
In connection with rubber it is in order to discuss the characteristics of 
chicle, the chemistry of which is alhed to that of rubber. The sources 
of rubber and chicle, as well as gutta percha and balata, are the milky 
juices or latices of a number of different trees, shrubs, and vines. The 
latices consist of watery emulsions holding in suspension minute globules 
of material, which coagulate under proper treatment and produce the 
commercial articles. 

The coagulated materials consist chiefly of hydrocarbons and resins 
with more or less carbohydrates, gums, proteids, tannins, mineral sub- 
stances, coloring matter, and water. The resinous constituents may be 
oxidation products of the hydrocarbons as it has been found that when 
the pure hydrocarbons are separated and purified, they take up oxygen 
with ease. 

The fundamental hydrocarbons are multiples of C10H16, and the hydro- 
carbons separated from all four sources are apparently closely alhed, if 
not identical, that from rubber is designated caoutchouc, that from gutta 
percha as gutta and the corresponding hydrocarbons from balata and 
chicle are termed bala-gutta and chicle-gutta. 

The latex yielding rubber is secreted by many different botanical 
species representing several families among which may be mentioned the 
Euphorbiaceas, Urticacess, Apocynacese, and Asclepiadaceae. Gutta 
percha, balata, and chicle are obtained chiefly from latices of species of 
the Sopotacess. 

Raw or unvulcanized rubber is soft, pliable, and elastic, at the ordi- 
nary temperature. When heated with boiling water or by mechanical 
working it becomes still softer. It is insoluble in water but is capable 
of absorbing up to 25 per cent of its own weight. It is insoluble in abso- 
lute alcohol but forms solutions with chloroform, benzol, toluol, carbon 
tetrachloride, carbon bisulphide, petroleum distillates, etc. Crude rubber 
contains a substance insoluble in the ordinaiy rubber solvents but which 
appears to swell up when subjected to their actions. 



512 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

The rubber hydrocarbon is attacked by the halogens and other oxidiz- 
ing agents. The oxidation product with ozone is a viscid substance 
which solidifies to a glassy explosive solid. 

CHICLE 

This coagulum from the latex of Achras Sapota is usually called gum 
chicle which is technically a misnomer, as the product comes under the 
class of gum resins and the resinous portion predominates. 

It forms a tenacious, firm, aromatic, and elastic mass, white or reddish 
in color. The red color sometimes develops when the latex is over- 
cooked in the process of concentration, but this is not always the case as 
some trees yield a gum-resin with a distinctly red color. 

Reports of the composition vary. Dieterich found 75 per cent resin, 
10 per cent gum, 9 per cent calcium oxalate, 5 per cent sugar and organic 
salts. 

Berry 1 states that the resins run from 35.6-55.78 per cent, hydro- 
carbons 10.39-13.84 per cent. He separates the resins into two groups, 
resin A insoluble in cold absolute alcohol, saponification value 129; and 
resin B soluble in cold absolute alcohol, saponification value 100.8. He 
found the saponification value of the combined resins to be 101.7-104. 
Acid value slight. 

Taylor reports an acid value of 52, no ethers or esters, 0.2 per cent 
ash, 82.7 per cent soluble in chloroform and 84.7 per cent soluble in benzol. 

Tschirch, 2 in his systematic manner, has examined chicle and reports 
16.8 per cent soluble in boiling water, 59.7 per cent in boiling alcohol, 
61.7 per cent in boiling acetone, 76.2 per cent in boiling ether, and 77.2 
per cent in chloroform. 

He treated chicle successively with boiling water, boiling alcohol, and 
chloroform, and examined the fractions. The water soluble portions 
yielded 9 per cent of gum. In the alcohol-soluble portion was found 
a-chiclalban, C24H40O, melting 219-221°; /3-chiclalban, CigHsoO or Ci 7 H 28 0, 
melting 158-159°; 7-chiclalban, C15H28O, melting 86-87°; and chicla- 
fluavil, CioHigO or C10H20O, melting 66-67°. In the chloroform portion 
was the hydrocarbon chiclagutta, C10H16 or CioHis, and chiclalbanan, an 
oxidation product, melting 55-57°. 

CHEWING GUM 

The principal components of chewing gum are chicle or some substi- 
tute, glucose, caramel, sugar, and flavor. Starch is often present in small 
quantity, as it is used in dusting the gum sheets to prevent their sticking 
to the rolls. 

1 Jour. Soc. Chem. Ind., 1904, 529. 2 Arch. Pharm., 1905, 243-378. 



GUMS AND RESINS 513 

Substitutes for chicle often comprise the base of chewing gum. They 
are usually prepared by mixing low-grade rubber, the resinous constitu- 
ents of crude rubber, gutta percha, or balata, the resene portions of other 
resins such as dammar, and vegetable wax or paraffin. 

Cauchillo gum is used as a masticatory similarly to chicle, and has 
been sold quite extensively to chewing gum manufacturers. It is of 
uncertain origin, but is reported to be derived from a tree in South America. 
It resembles chicle in physical appearance and is often denominated as 
chicle in the trade. Chewing gums are medicated with pepsin and to a 
lesser extent with strychnin or some other bitter substance. The latter 
type of product is used for the purpose of breaking up the tobacco habit. 
Occasionally one will meet with unusual mixtures having a chewing gum 
base, as instanced by one containing a large percentage of coca leaf and 
which was quite extensively sold several years ago. 

A complete analysis of a gum includes determinations of the propor- 
tional amounts of the base, sugars, and medicament, a test for digestive 
power, the amount of moisture and other volatile components, and ash. 
As a general thing the drug analyst is concerned only with the medicinal 
constituents, and in the case of pepsin gums it is often only a question of 
determining whether or not the sample will act on coagulated egg albumin. 

For the analysis several sticks of the sample should be broken up 
into small pieces and thoroughly mixed. 

The moisture and volatile matter are determined with a 1-2 gram 
sample, drying at 100-110°. The residue is ignited and weighed as ash. 
Good chicle gum leaves an ash consisting chiefly of calcium carbonate, 
no sand or other gritty material being present. 

To prepare a sample for determining the sugars, etc., about 5 grams 
are transferred to a flask or stoppered bottle, covered with chloroform 
and shaken until the resinous ingredients have dissolved. The solution 
is filtered, the insoluble substance washed with chloroform and then allowed 
to dry. The dry residue is digested with cold water, and filtered from 
any insoluble material. Solution may be hastened by transferring as 
much as possible to a small mortar and grinding the material in the pres- 
ence of the solvent. The solution is finally made up to a definite volume 
and the sugars determined in the usual way. 

An aliquot of the solution is then adjusted to the proper strength with 
hydrochloric acid, added to a bottle containing a weighed amount of egg 
albumin and a pepsin test conducted as described in the chapter on " Diges- 
tives." If digestive agents other than pepsin are suspected the appro- 
priate procedure will necessarily follow. 

If strychnin salts or those of other alkaloids are present they will be 
found principally in the aqueous solution though some portion will go 
into the chloroform. The alkaloids are freed from the aqueous solution 



514 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 

by making alkaline and shaking out with chloroform. From the chloro- 
form solution containing the gum base, any alkaloids can be separated 
by shaking out with a little normal sulphuric acid and then removed from 
the acid by making alkaline and shaking out with chloroform. 

F. J. Andress 1 employs a scheme for testing the gum base in which 
he masticates a weighed sample until the sugar and flavor have disappeared, 
dries it in an oven and then weighs. The procedure then goes ahead as 
follows : 

Weigh off a 2 or 3-gram sample in an alundum extraction thimble, 
using a small cotton plug to close up the open end. Extract with acetone 
in a Soxhlet apparatus for five or six hours. Allow the extraction to proceed 
until the acetone becomes colorless as it siphons over and then continue 
the extraction until about ten more portions have been returned to flask. 
After the extraction is completed, disconnect the apparatus and dry 
thimble in steam oven to constant weight. Distill off the acetone in 
flask, dry in oven, and weigh. 

Residue in Thimble. — If a pure chicle has been used, this will be a 
light reddish color and somewhat brittle. Should it, however, be a black, 
elastic body, substitution in all likelihood has been employed in the manu- 
facturing process. To make a proper comparison, it is advisable to extract 
some pure chicle gum and compare the residues obtained. 

Extract. — This may consist entirely of the resinous matter in chicle. 
It will also contain any wax or oil used in compounding the substitute 
or finished gum. Weigh off a 1-gram sa,mple of the acetone extract, transfer 
to a 300-mil Erlenmeyer flask and determine the saponification value. 
Good results may be obtained by using 5 mils of benzene to take the resins 
into solution and then adding 20 mils N/2 alcoholic KOH for the saponi- 
fication. Run a blank, using the same amounts of benzene and KOH. 
A funnel with the stem cut short is a very satisfactory reflux condenser. 

Replace any alcohol lost in the boiling, adding the same amount to 
both flasks. One hour's boiling is usually sufficient to complete the saponi- 
fication. Add 100 mils of cold water (recently boiled and cooled) 1 mil of 
phenol phthalein solution and titrate with N/10 HC1. Calculate the 
number of milligrams of KOH required to saponify 1 gram of resin. Most 
of the resins from the rubber gums likely to be used, will have a saponi- 
fication value of 87 to 100 milligrams of KOH. 

Waxes. — Use a 1-gram sample of the resinous extract. Warm with 
about 50 grams of glacial acetic acid. The resins, fatty matters, and 
mineral oils will go into solution, while the paraffin, on cooling, separates 
out almost quantitatively. Filter on a tared filter, wash three or four 
times with cold, glacial acetic acid and then follow with four or five 
washings with cold water, to remove the acid. Dry in steam oven and 
1 The Chemist Analyst, Nov., 15, 1916, page 5. 






GUMS AND RESINS 515 

weigh. Use a stoppered weighing bottle in drying the filter and make 
the drying and final weighing in the same bottle, to prevent loss of wax, 
which in drying may melt and pass through the filter. 

PLASTERS 

Plasters consist of a medicament incorporated in a base of some resin- 
ous character and spread upon cloth or paper. 

Plaster mass or the base on which the adhesive character depends, 
varies in composition. Among the combinations may be mentioned the 
following : 

Rubber, Burgundy pitcn and olibanum. 

Lead oleate or lead plaster as it is commonly called. 

Soap, lead plaster, and colophony. 

Lead plaster, yellow wax, colophony, ammoniacum, myrrh. 

Bdellium, olibanum, turpentine, and storax. 

Individual plasters or those to which specific names are applied include : 

Ammoniac plaster composed of ammoniacum and acetic acid 

Aromatic plaster composed of lead plaster with cloves, cinnamon, 
ginger, capsicum, camphor, and cotton seed oil. 

Camphorated Brown Plaster (Camphorated Mother Plaster) com- 
posed of lead oxide, olive oil, yellow wax, and camphor. 

Galbanum plaster, composed of galbanum, turpentine, Burgundy pitch, 
and lead plaster. 

Pitch plaster, composed of Burgundy pitch, olibanum, colophony, bees- 
wax, and olive oil. 

Canada pitch plaster, composed of Canada balsam and yellow wax. 

Resin plaster, composed of colophony, lead plaster, and yellow wax. 

Lead Plaster (diachylon) prepared with lead oxide and olive oil which 
yields practically lead oleate. 

The plaster masses described above or the named types of plasters 
are employed in making up the various medicated plasters. The following 
list includes the principal forms of medicated plasters which will be en- 
countered in analytical work: 

Aconite with base of resin plaster. 

Ammoniacum with mercury and oleate of mercury in a lead plaster 
base. 

Arnica in resin plaster. 

Asafetida in a base of lead plaster, galbanum, and yellow wax. 

Belladonna in resin or soap plaster. 

Capsicum in resin plaster. 

Compound tar plaster composed of colophony, tar, Podophyllum resin, 
Phytolacca, and Sanguinaria. 



516 GLUCOSIDES, GLUCOSIDAL DRUGS AND NATURAL DRUGS 



Iron or Strengthening plaster composed of ferric hydroxide in Bur- 
gundy pitch and lead plaster. 

Mercurial plaster, composed of mercury and mercury oleate in lead 
plaster. 

Menthol in resin and beeswax. 

Antimonial composed of tartar emetic in Burgundy pitch. 

Opium in Burgundy pitch and lead plaster. 

Cantharides, composed of cerate of cantharides and Burgundy pitch 
or powered cantharides in beeswax and soap plaster. 

Lead iodide in lead plaster and resin. 

Zinc plaster consists of zinc oleate and palmitate. 

Mustard plaster consists of powdered black mustard deprived of its 
oil incorporated in a rubber base. 

Adhesive plaster consists of rubber, resins, and waxes with a filler of 
absorbent powder such as orris root or starch. 

Court plaster consists of a mixture of isinglass, glycerin, and benzoin. 

Analysis of Plasters. — The analysis of a plaster of alleged composition 
for the purpose of identifying its medicinal constituents is neither difficult 
nor complicated. A detailed scheme which is both simple and accurate 
has been described in my work " The Qualitative Analysis of Medicinal 
Preparations." 

After separating the medicinal components from the plaster base the 
character of the latter usually reveals itself more or less accurately by 
conducting the routine resin analysis. The values obtained can then be 
compared with the data recorded in the preceding pages. 



Part IV 

ORGANIC SUBSTANCES OTHER THAN 
ALKALOIDS AND GLUCOSIDES 



CHAPTER XV 
HYDROCARBONS— ALCOHOLS— ETHERS 

A Classification of a group of substances under the term "synthetic" 
without reference to their chemical relationship is not feasible, and the 
limitations of the term " synthetic " are not easy to define. Certain sub- 
stances are undoubtedly " synthetic " in all respects and, might easily 
be considered under such a heading; thus we have acetanilid, acetphene- 
tidin, sulphomethan and saccharin, which, while they belong to definite 
groups of substances constitutionally, might be treated under one group 
from the standpoint of the analyst of medicinal products. On the other 
hand we have acetyl morphin, diacetylmorphin, eucain, anesthesin, 
euquinin, and homatropin, which are all products of the laboratory and 
yet are best treated under other headings, the morphin derivatives con- 
jointly with the opium basis, the anesthetics with cocain, quinin deriv- 
ations with quinin, and homatropin with its parent substance atropin. 
Again we meet with iodoform, dithymoldiiodide, bismuthbetanaphtho- 
late and mercurol, which fall more naturally under the general consider- 
ation of iodine, bismuth, and mercury derivatives. It was therefore 
decided at the outset to arrange the material as nearly as possible accord- 
ing to its chemical relation, though deviations from this procedure must 
necessarily occur. 

There have been a vast number of " new remedies " or " synthetics " 
evolved during the last two decades, but fortunately for the drug analyst 
the substances which are used in mixture are comparatively few and in 
most cases their separation and detection is not difficult. By far the 
greater number of these substances are dispensed by themselves either 
in their pure condition in prescriptions, or in pills, tablets, and capsules, 

517 



518 ORGANIC SUBSTANCES 

with some simple diluent or excipient. Their melting-points and general 
properties have been carefully determined, and after a few tests to 
determine their character, they may be assigned to their proper class 
and identified in this connection. The writer wishes to call especial 
attention to Professor Mullikin's work, "The Identification of Organic 
Substances," which will furnish valuable aid in pointing to the identity 
of an individual. 

The substances of this group which have an extended use in medicine 
include acetanilid, acetphenetidin, antipyrin, chloroform, sulphomethane, 
sulphonethylmethane, phenolphthalein, saccharin, hexamethylenamin, 
chloral, acetyl salicylic acid, oxyquinolin, methylene blue, guaiacol car- 
bonate, salol, salophen, resorcinol, and perhaps a few others. In the general 
scheme of drug analysis which is outlined in my work "Qualitative 
Analysis of Medicinal Preparations," the fractions in which these products 
will be found are indicated, and in the accompanying work there is given 
a detailed description of their properties and tests and an arrangement 
of the substances as nearly as feasible according to their chemical 
constitution. 

Many of the substances described in this section are not themselves 
drugs, or medicinal agents, but as they may result from decomposition 
of other products which are drugs, and as their identification or determi- 
nation may be important factors in the particular research under consider- 
ation, it is important that they should be discussed, and sufficient data 
assembled to aid the worker, without the necessity of consulting other 
works on organic chemistry. 

HYDROCARBONS 

The aliphatic hydrocarbons are of little moment to the drug chemist. 
The gaseous members of the methane, ethylene, and acetylene groups 
may be passed over unnoticed. The liquid and solid hydrocarbons of 
the methane group occur in petrolatum and paraffin 

The saturated hydrocarbons of the aliphatic series are markedly indif- 
ferent substances. They are unaffected by acids or alkalies, are permanent 
in the air and sunlight, insoluble in water and but sparingly so in alcohol, 
though they go into solution with ease in ether and chloroform. Deriva- 
tions of place of some of the lower members are used medicinally, but 
none of them can be prepared directly from the hydrocarbons themselves. 

The hydrocarbons of the methane series have an important place in 
medicinal chemistry in the form of petrolatum or vaseline and in liquid 
petrolatum, white neutral oil, and albolene. 

Petrolatum or vaseline varies in color from white to dark red, but the 
pharmacopoeial product cannot be darker than light amber. It is a soft, 



HYDROCARBONS— ALCOHOLS— ETHERS 519 

unctuous mass, practically odorless and tasteless, but giving a faint 
petroleum-like odor on heating. It may be slightly fluorescent and is 
transparent in thin layers. Petrolatum melts 45°-50°, and is lighter 
than water. When heated to 60° its specific gravity is .820-850. It 
is insoluble in water, but will emulsify with it if the mixture is stirred 
sufficiently. It is but slightly soluble in 95 per cent alcohol, but dissolves 
in boiling absolute alcohol and in ether, chloroform, petroleum ether, 
benzol, carbon disulphide, oil of turpentine, fixed and volatile oils. 

Petrolatum is unsaponifiable and has no iodin value if pure. It 
resists the action of 85 per cent sulphuric acid, and is in general a very 
indifferent substance. 

Liquid petrolatum may be water white to slightly yellowish with 
a bluish fluorescence. Its specific gravity is from .870-.940 at 25° 
C. and in all other respects its properties are the same as those of the 
solid form. 

Petrolatum is the base of a great variety of ointments, cold creams, 
and petroleum emulsions. The liquid form has acquired considerable 
reputation in bowel troubles. 

Paraffin which is a mixture of hydrocarbons of still higher melting- 
points, is a white, translucent substance of wax-like consistency. It is 
used to a large extent in ointments, pastes, and creams, acting as an agent 
to give the product its proper consistency. 

Mixtures of petrolatum and ammonium oleate are marketed under 
proprietary names and are combined with iodin, sulphur, ichthyol, etc. 

The determination of hydrocarbons in pharmaceutical mixtures and 
toilet preparations resolves itself practically into a measure of the unsa- 
ponifiable matter. The most satisfactory procedure for accomplishing 
this is one which was worked out in my laboratory by T. M. Rector, 
and the details follow : 

Weigh from 5 to 10 grams of the oil or fat into a 300-mil Erlenmeyer 
flask, add 100 mils of alcoholic potash (40 grams per liter) and heat on 
the water-bath until saponification is complete. A small funnel in the 
neck of the flask will serve as a reflux condenser. After saponification, 
which usually takes from thirty to forty-five minutes, the hot soap solu- 
tion is poured into a 16-oz. Squibb separator and the flask rinsed with 
two 25-mil portions of 95 per cent alcohol, making a total of 150 mils of 
95 per cent alcohol. The separator is cooled to room temperature by 
shaking under the tap and 75 mils of light petroleum ether added. The 
petroleum ether dissolves in the alcohol, forming a clear solution. 

About 125 mils of water are next added and the mixture shaken. At 
this point the petroleum ether will separate and rise to the surface of the 
alcohol-water mixture in a clear layer. The soap solution is drawn off 
into a second separator and extracted twice with 50-mil portions of petro- 



520 ORGANIC SUBSTANCES 

leum ether. The combined petroleum ether extracts are filtered into a 
tared beaker and evaporated on the water-bath. The residue is dried 
in a vacuum desiccator and weighed. 

To make a successful determination, the following points are essential: 

1. Use a petroleum ether completely volatile under 80°. 

2. The alcohol content of the soap solution after dilution with water 
should be very close to 55 per cent by volume. It is necessary to know 
the volume of the alcoholic potash solution as well as the amount of alco- 
hol used in rinsing the flask. A lower content of alcohol than 50 per cent 
will result in emulsions, while a higher percentage than 60 will cause the 
retention of a large part of the petroleum ether in solution. 

3. A beaker should be used for the final evaporation. The unsaponi- 
fiable matter will " creep " over the edges of an evaporating dish and 
cause low results. 

4. The residue should be placed in a vacuum desiccator immediately 
after the petroleum ether has evaporated, to avoid loss by volatilization. 

This method will of course give all of the unsaponifiable matter, includ- 
ing alcohols from waxes. These may be separated by boiling with acetic 
anhydride under a reflux and repeating the shaking-out process. 

Some of the essential oils, notably oils of rose and chamomile, contain 
hydrocarbons in sufficient quantity to cause a solidification of the whole 
or a part of the sample. They are called stearoptenes, and are evidently 
mixtures of paraffins or defines, the identity of which has not yet been 
ascertained. The stearoptene from rose oil melts 35°, and when distilled 
in vacuo separates into two fractions, melting 22° and 40-41° respectively. 

Other essential oils in which hydrocarbons are known to occur include 
Arnica flower, dill, caraway herb, neroli, sassafras leaf, gaultheria, betula, 
and wild bergamot. 

Benzol, C 6 H 6 

Benzol, benzene, phenyl-hydride or coal-tar naphtha is a colorless, 
mobile, highly refractive liquid, with a characteristic odor, specific gravity 
.883-885 at 15°, boiling 80-81°, soluble in alcohol, ether, chloroform, 
glacial acetic acid, acetone and oils and insoluble in water. Below +6° C. 
it is a crystalline solid. Concentrated nitric acid at ordinary temperature 
converts benzol into nitrobenzol, C6H5NO2, a substance with a character- 
istic odor, boiling 205°, known as " Oil of Myrbane," Sulphuric acid 
converts benzol into benzene-sulphuric acid, C6H5SO3H. Chlorin and 
bromin act on benzol at moderately high temperatures or in presence 
of direct sunlight to form hexa addition compounds, CeHeXe. At ordinary 
temperature or in the absence of sunlight substitution products are formed, 



HYDROCARBONS— ALCOHOLS— ETHERS 521 

In medicine benzene is used as an antispasmodic in whooping cough 
and influenza. It is dispensed in capsule form, as an emulsion, and mixed 
with sugar. 

Cymene. Methylisopropyl Benzene, C^H^iCHs) (C3H7) 

Cymene is capable of existing in three modifications, but the para 
form is the only one of interest to the drug chemist. It occurs in oil of 
thyme, and has been reported in the analysis of oils of Monarda punctata, 
Cuminum cyminum, Cicuta virosa and Origanum. 

Para-cymene is a colorless liquid boiling 175-176° C, inactive to 
polarized light, with an agreeable odor resembling- oil of lemons. Its 
specific gravity is .86 at 15°. Chromic acid or dilute nitric acid eventually 
convert it to terephthalic acid, which serves as a means for its identi- 
fication. To carry out this reaction it is boiled under a reflux for thirty 
hours with excess of strong chromic acid mixture, or until the mixture 
dropping from the condenser is no longer oily. After cooling and dilut- 
ing with water, the insoluble terephthalic acid is filtered off and purified 
by solution in ammonia, boiling with animal charcoal and reprecipitation 
by hydrochloric acid. The purified acid sublimes without melting. 

Cymene may be identified by converting it to oxyisopropyl benzoic 
acid. It is treated with potassium permanganate in the proportion of 1-6 
in a 4 per cent aqueous solution and boiled under a reflux. When the 
oxidation is complete, it is filtered, the filtrate evaporated, the potassium 
salt extracted with alcohol, the solvent evaporated, and an aqueous 
solution precipitated with dilute sulphuric acid, the filtered acid being 
recrystaUized from alcohol. Melting-point, 155-156°. 

Cinnamene or Styrene, (C 6 H 5 CH = CH 2 ) 

Styrene is an unsaturated hydrocarbon having the composition of 
a phenylethylene. It occurs in liquid storax and is a colorless, highly 
refractive liquid, boiling 144-145° C, with a pleasant odor. It poly- 
merizes readily to meta-styrene. 

THE CYCLIC HYDROCARBONS 

The cyclic hydrocarbons are of considerable interest to us owing to 
their prevalence in essential oils, many of which are used to a greater 
or less extent in drug products, and whose identity may sometimes be a 
question of importance. 

These hydrocarbons may be considered as polymers of pentine, CsBfe, 
and have been arranged by Wallach in the following classes : 



522 ORGANIC SUBSTANCES 

A. Pentines or hemiterpenes, CsHg, as isoprene and valerylene. 

B. Dipentines or terpenes, (CsHg^ or Ci Hi 6 , including pinene ; 
limonene, fenchene, camphene, phellandrene, etc. 

C. Tripentines or sesquiterpenes, C15H24, as cedrene and cubebene. 

D. Diterpenes, C20H32, as colophene and copaivine. 

E. Polyterpenes, (CsHs)**, as the polyprene of caoutchouc. 

Those of the B and C classes are of importance in this work. The 
chemistry of the diterpenes and polyterpenes is still in need of much 
extended research. 

The terpenes are isomerides of the moleculer formula C10H16. They 
may nearly all be derived from a hydrocarbon terpane or menthane, 
C10H20, which has the composition of a methyl isopropyl cyclohexane. 

•CH2 CIl2\ /CH3 . 

CH3— CH< >CH— CH< 

X CH 2 — CH 2 / X CH3 

which is closely related to cymene and from which it may be derived by 
reducing the aromatic nucleus. It is convertible to cymene by oxidation. 

The terpenes, C10H16, which are the intermediate between cymene, 
C10H14, and terpane, C10H20, differ from the latter by four atoms of hydro- 
gen in the molecule. They divide themselves into two groups contain- 
ing in addition to the hexamethylene ring. 

I. Two double bonds as in the monocyclic terpenes. 
II. A double bond and a second ring system, as in the dicylic terpenes. 

The structure of the monocylic terpenes is fairly well established. 

/>CH — CH2 \ /CH3 

Limonene and Dipentene CH3 — C\ yCR — C/ 

X CH 2 — CH</ ^CH 2 

x,CH2 — CH2\ /CH3 

Terpinolene CH 3 — Cf >C=C< 

X CH 2 — CH 2 / X GH3 

/CH2 — CH2\ /CH3 

Beta-phellandrene CH 2 =C< >C— CH/ 



CH^CH / X CH 



3 

// CH — CH ^ /CH3 

1 Terpinene CH 3 Cf >C— CH < 

X CH 2 — CH 2 / X CHs 

x/CH — CH2K /CH3 

1 Alpha-phellandrene CHsCf >CH— CH< 

XJH= CH / XJHa 

1 In these two both double bonds are in the nucleus, and they may be described as 
dihydro-p-cymenes. 



HYDROCARBONS— ALCOHOLS— ETHERS 

/CH 3 



523 



C 



Sylvestrene 



CH3— C 



// 



CH— CH 
^CHs-CHs/ 



\ 



CH S 



CH 2 



The structural formulas of the' dicyclic terpenes is less clearly estab- 
lished. Pinene is probably 




CH 3 



and its hydrochloride is 



CH 5 



CH- 

I 
CH 3 — C- 

I 
CH 2 C- 



— CH 2 

CH 3 

-CHC1 



Bornylene is probably 



CH3 

CH 2 — CH- 

I 
CH 3 — O 

I 
CH 2 - 



-CH 



-CH 3 
— CH 



-C- 

I 
CH3 

The monocyhc terpenes are characterized by generally forming tetra- 
bromides, while the dicyclic terpenes usually form only dibromides, though 
they often add on 2HBr owing to the rupture of the ring systems by the 
acids. 

With the exception of camphene, which is a solid, the terpenes are 
light, colorless, volatile, odorous liquids. They resemble each other closely 
in their physical properties, and are difficult to identify by resorting to 
these characteristics, and this is further complicated by the ease with 
which one terpene will change into another or from one modification to 
another. 

By resorting to chemical means, better results will be obtained, and 

1 A meta-compound analogous to Limonene or Dipentene. 



524 ORGANIC SUBSTANCES 

the formation of one or more of the following compounds will often serve 
to identify the terpene under investigation. 

The bromides may be formed by dissolving 1 volume of the terpene in 
4 volumes of alcohol and 4 of ether. The solution is well cooled by ice 
and .7 volume of bromin is slowly added. The Crystalline precipitate 
is washed with cold alcohol and recrystallized from ether. 

The nitrosochlorides may be prepared by dissolving the terpene in 
about 2\ times its volume of glacial acetic acid, cooling in a mixture of 
ice and salt and adding the same quantity of ethyl or amyl nitrite. This 
mixture, after thorough cooling, is slowly treated with half its volume 
of a mixture of equal volumes of glacial acetic and concentrated hydro- 
chloric acids, allowing time for the blue color to disappear before adding 
more acid. After fifteen minutes the crystals are filtered, washed with 
alcohol, dried at room temperature, dissolved in the least possible quantity 
of chloroform, from which solvent the nitrosochloride is reprecipitated 
by adding methyl alcohol. After drying its melting-point and micro- 
scopic appearance may be determined. 

The nitrosobromides may be formed in the same way. 

On treating the terpene nitrosochlorides with alcoholic potash or 
cautiously heating them alone, the elements of hydrochloric acid are 
removed and products of the composition C10H15NO obtained. 

The mono-hydrochlorides are formed by passing a stream of dry hydro- 
gen chloride through the dry terpene. 

The dihydrochlorides are produced by the action of moist hydrogen 
chloride. They are conveniently prepared by mixing a solution of the 
terpene in glacial acetic acid with glacial acetic acid saturated with hydro- 
gen chloride. The dihydrochloride may be crystallized out of a mixture 
of alcohol and ether. 

The dihydrobromides may be prepared in the same way. 

The tetrabromides are prepared by dissolving the terpene in glacial 
acetic acid and adding bromide. The tetrabromide is recrystallized from 
ethyl acetate. 

Sesquiterpenes, C15H24 

The sesquiterpenes are viscous substances with higher specific gravity 
and boiling-points than the terpenes. When treated with bromin or 
iodine and the product distilled with water, cymene is produced. 

Many sesquiterpenes have been described, but the individuality of 
all but a few is questionable. Caryophyllene is well established as the 
sesquiterpene of oil of cloves and it also occurs in copaiba. 

The sesquiterpenes are characterized by the formation of dihydro- 
chlorides and tetrabromides; nitrosochlorides (NOC1), nitrosates (N2O4) 
and nitrosites (N2O3). 



HYDROCARBONS— ALCOHOLS— ETHERS 



525 



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HYDROCARBONS— ALCOHOLS— ETHERS 527 



Terebene 

Terebene is a pharmacopoeial product consisting of dipentene and 
other hydrocarbons, obtained by the action of sulphuric acid on oil of 
turpentine and subsequent rectification with steam. It is a colorless 
limpid liquid, boiling 160-170° C, having an agreeable thyme-like odor. 
Its specific gravity is .860-.865 at 25° C, and it is only slightly soluble 
in water, but dissolves readily in alcohol, ether, carbonbisulphide, and 
glacial acetic acid. It is inactive to polarized light and thereby differs 
markedly from oil of turpentine. On exposure to fight and air it becomes 
resinified and acquires an acid reaction. 

It is used in a variety of ailments, including chronic bronchitis, flat- 
ulency, uterine cancer, genito-urinary diseases, and tubercular troubles. 



Naphthalene, Ci H 8 

Naphthalene or tar camphor is a white scaly or crystalline substance, 
with a characteristic coal-tar odor, melting 79-80°, boiling 218°, insoluble 
in water, but to which it imparts its odor and taste on boiling, soluble in 
alcohol, ether, chloroform, fixed and volatile oils. Its vapor is inflam- 
mable, burning with a luminous, smoky flame, and it is volatile slowly 
at the ordinary temperature. 

It yields a nitro-derivative and a sulphonic acid in a similar manner 
to benzol, and on boiling with dilute nitric or chromic acid is slowly 
oxidized, yielding carbon dioxide and orthophthalic acid. When dis- 
solved in alcohol and treated with an alcoholic solution of picric acid, 
yellow crystalline naphthalene picrate, CnH6-C6H2(N02)30H, melting 
149°, is formed. 

Naphthalene possesses a number of therapeutic properties, but it has 
a limited use as a medicament. It has been employed in intestinal catarrh 
and inflammation, tapeworm, cholera, typhoid, and chronic bronchitis. 
Externally it may be encountered in ointments for skin diseases. 



Anthracene, Ci 4 Hi 
Anthracene, with structural formula 




528 ORGANIC SUBSTANCES 

crystallizes in colorless, lustrous plates, with blue fluorescence, melting 
213°, boiling 360°. It is freely soluble in hot benzol, but only slightly in 
alcohol and ether. A saturated alcoholic solution mixed with an alcoholic 
solution of picric acid gives a precipitate of ruby-red needles of anthracene 
picrate, melting 138°. This compound may be resolved into its compo- 
nents when treated with considerable alcohol. 

Anthracene itself has no interest to the drug chemist, but it is the 
basic substance of an important series of principles which are the active 
medicinal agents of the laxative drugs Cascara sagrada, Senna, Rhubarb, 
Rhamnus fragula, and Aloes. These principles are hydroxyanthra- 
quinones. 

/ co \ 

Anthraquinone, C6H4C }CqH4, is formed by oxidizing anthracene 

XJCK 
with chromic acid. It forms pale yellow needles, melting 277°, and sub- 
limes at higher temperature in long sulphur yellow needles. It is very 
stable and is attacked only with difficulty by oxidizing agents, sulphuric, 
or nitric acids. 

Anthraquinone forms sulphonic acids when heated with sulphuric 
anhydride. 

When a trace of anthraquinone is mixed with dilute sodium hydroxide, 
a little zinc dust added and the mixture boiled, an intense red color is 
produced, but on shaking in contanct with air the solution is decolorized. 
Oxanthranol is formed, which dissolves in alkali to a red solution, but 
in contact with air it is oxidized to anthraquinone, which separates as a 
white flocculent precipitate. 

Anthraquinone on treatment with powerful reducing agents is finally 

/C(OHV 
converted to anthranol, C^ECk /C6H4. 

X CH / 

.COIL .OH 

Dihydroxyanthranoloranthrarobin,C6H4\ J>CH2<f , is used as 

X CH-/ X)H 

an antiseptic in skin diseases. It is soluble in weak alkalies and hot alco- 
hol, slightly in ether and chloroform. 

Alizarin 

.... . / co \ 

Alizarin is a-/3-dihydroxyanthraquinone, CeH4\ >CeH2(OH)2. It 

is a dark-red substance, melting 282°, almost insoluble in water, moderately 
in alcohol and readily in alkaline liquids, forming reddish-violet solutions. 
When distilled with zinc dust it is reduced to anthracene and with acetic 
anhydride it forms a diacetate, melting 180°. 



HYDROCARBONS— ALCOHOLS— ETHERS 529 

Alizarin yields insoluble lakes with metallic oxides, the ferric compound 
is violet black, the calcium blue, the tin and aluminum different shades of 
red. 

A piece of calico will be colored yellow by a solution of alizarin, but 
not fast. But if one previously mordanted with aluminum salt be used, 
a fast red will be formed on the cloth, or with iron a dark purple. The 
mordanting often requires two operations, first the cloth is soaked or boiled 
in an acetate or sulphate bath of the metal, then immersed in a weak alkali 
(ammonia, sodium carbonate, or lime) and then dipped in the alizarin 
solution. 

These facts will be of service to the analyst who is concerned with the 
testing of the oxyanthraquinone principles of the aforesaid drugs, 

Purpurin 

Purpurin is a-^a'-trihydroxyanthraquinone. Its isomeride, anthra- 
/C(X /OHa 

purpurin, C6H3(OH)<^ }CoH 2 <f in the form of the diacetate, is 

X C(K X)H/3 

known as Purgatol, a yellow, tasteless powder, soluble in alkalies, but insol- 
uble in water or dilute acids. It is used as a purgative. Anthrapurpurin 
forms yellowish-red needles, melting 330° C. 

THE ALCOHOLS 

The monohydric alcohols may be regarded as derived from the paraffins 
by the substitution of the monovalent hydroxyl group OH for one atom of 
hydrogen. 

Methyl alcohol CH3OH derived from methane, CH3H. 

Ethyl alcohol C2H5OH derived from ethane, C2H5H. 
The dihydric alcohols or glycols may be considered as dihydroxy 
derivatives of the paraffins, forming an homologous series of the general 
formula C n H2 W (OH)2, the simplest of which is ethylene glycol. 

Ethylene glycol, C2H4(OH)2, from ethane, C2H4H2. 
The trihydric and polyhydric alcohols stand in the same relation to the 
glycols as the latter to the monohydric alcohols. 

Propenyl alcohol, or glycerol, CsH5(OH)3 from propane, C3H5H3. 

Erithritol, C 4 H 6 (OH) 4 , from C 4 H 6 H4. 

Mannitol, C 6 H 6 (OH) 6 , from C 6 H 8 H 6 . 
The alcohols play an exceedingly important part in drug and medicinal 
chemistry both as remedial agents and vehicles. The monohydric alcohols 
are represented by methyl and ethyl alcohol, and the trihydric alcohols 
by glycerol. The glycols themselves are not of great importance, but 
certain of the oxidation products, lactic, oxalic, succinic, tartaric, and 
citric acids, are of great value. 



530 ORGANIC SUBSTANCES 

There are three classes of alcohols — primary, secondary, and tertiary. 
The primary alcohols may be said to be derived from methyl alcohol by 
substituting for one of the three hydrogen atoms united to the carbon, 
a hydrocarbon radicle, RCH2OH. The secondary alcohols may be con- 
sidered methyl alcohol, in which two of the hydrogen atoms united to 
the carbon are replaced by two hydrocarbon radicles R 2 CHOH, and 
similarly in the tertiary alcohols all three hydrogen atoms are replaced 
by hydrocarbon radicles, R3COH. 

General Properties of the Monohydric Alcohols. — The lower members 
are colorless, neutral liquids with a burning taste and characteristic odor, 
miscible with water in all proportions and with nearly all organic liquids. 
As the molecular weight increases they change to oily liquids immiscible 
with water, and finally to waxy and crystalline solids. 

The boiling-points increase with the molecular weight in the case of 
the primary alcohols, but the progression is broken with the isomeric forms, 
for instance primary propyl alcohol boils at 97° and primary butyl alco- 
hol 117°, while tertiary butyl alcohol boils 83°, the same as does the 
secondary isopropyl alcohol. 

The chemical reactions of the monohydric alcohols are with few excep- 
tions due to the presence of the hydroxyl group, in many reactions they 
conduct themselves as alkyl substitution products of water, and in 
others they are analogous to metallic hydroxides. With sodium and potas- 
sium, hydrogen is evolved, but the resulting product is not a stable salt, 
being decomposed by water. 

They produce ethereal salts with acids, yield halogen derivatives with 
phosphorus haloids, and are converted into olefines by dehydrating agents. 
On oxidation primary alcohols are converted to aldehydes and then into 
fatty acids, and secondary alcohols to ketones, both yielding oxidation 
products with the same number of carbon atoms as the original alcohol. 
Tertiary alcohols are decomposed, giving simpler acids or ketones. 

Methyl Alcohol 

Methyl alcohol has only a Kmited use in medicinal preparations. It 
is employed as the vehicle in some Hniments and " balsams," and has 
occasionally been found in liquids intended for internal administration. 
Small quantities will sometimes be found in presence of a much greater 
proportion of ethyl alcohol, indicating that denatured alcohol has entered 
into the composition of the product under investigation. 

Ordinary wood alcohol contains varying amounts of acetone and other 
volatile constituents occurring in wood distillate, and has a rank, unpleasant 
odor. There are several grades of the purified product, and those of the 
greatest purity are water white in color, with a characteristic pleasant 
odor differing somewhat from that of ethyl alcohol. The pure product 



HYDROCARBONS— ALCOHOLS— ETHERS 53 1 

has a specific gravity of .796 at 15° C, boils 65-66°, and is miscible in all 
proportions with water, ether, and alcohol. It is inflammable, burning 
with a pale, non-luminous flame, and its vapor forms an explosive mixture 
with air or oxygen. Sodium and potassium dissolve readily with the 
formation of methylates and evolution of hydrogen, these methylates are 
extremely deliquescent and are immediately decomposed by water with 
regeneration of methyl alcohol. Methyl alcohol gives methyl chloride 
when saturated with hydrogen chloride gas, or on treatment with the 
chlorides of phosphorus. It gives methyl hydrogen sulphate when warmed 
with concentrated sulphuric acid, and normal methyl oxalate with oxalic 
acid. On oxidation it is converted into formaldehyde, which latter is 
further oxidized to formic acid. It does not give the iodoform reaction 
when warmed with iodine and alkali. 

High-grade methyl alcohol for commercial purposes should leave but 
a trace of residue on evaporation, give no iodoform reaction indicative 
of acetone, no color with sodium hydroxide solution, 1.3 sp. gr., and not 
discharge the color of N/10 permanganate. 

The drug analyst will be frequently called upon to identify methyl 
alcohol, which is easily accomplished by converting a portion of it into 
formaldehyde and identifying the latter by some characteristic color 
reaction. There are many tests described and as many procedures for 
obtaining the reactions. No attempt will be made to enumerate or repeat 
them all. 

To begin with, the alcohol under investigation must be obtained in 
a condition which is as nearly pure as possible. If it is part of the formula 
of a complex medicine it must be distilled from the mixture, and if the 
distillate contains volatile oils they must be removed by shaking out with 
petroleum ether in the presence of sodium chloride and at a moderate 
dilution, and the alcohol again distilled from the salt. 

Probably the best known test is that obtained by subjecting the dis- 
tillate to the oxidizing influence of a red-hot copper spiral, and subsequently 
noting the appearance of a brilliant crimson color on adding sulphuric 
acid containing resorcinol. 

Another good method depends on the formation of formaldehyde by 
the action of permanganate, the distillation of the aldehyde, and its identi- 
fication by morphin dissolved in sulphuric acid. This procedure is 
really a combination of a method described by Henkel and one by Deniges. 

The resorcinol test is carried out as follows: 

Oxidize 10 mils of the liquid in a test-tube as follows: Wind copper wire 
1 mm. thick upon a rod or pencil 7 to 8 mm. thick, in such a manner as to 
inclose the fixed end of the wire, and to form a close coil 3 to 3.5 cm.long. 
Twist the two ends of the wire into a stem 20 cm. long, and bend the stem at 
right angles about 6 cm. from the free end, or so that the coil may be 



532 ORGANIC SUBSTANCES 

plunged to the bottom of the test-tube, preferably about 16 mm. wide and 
about 16 cm. long. Heat the coil in the upper or oxidizing flame of a Bunsen 
burner to a red heat throughout. Plunge the heated coil to the bottom 
of the test-tube containing the diluted alcohol. Withdraw the coil after 
a second's time and dip it in water. Repeat the operation from three 
to five times, or until the film of copper oxide ceases to be reduced. Cool 
the liquid in the test-tube meanwhile by immersion in cold water. Deniges 1 
oxidizes the methyl alcohol to formaldehyde by the use of permanganate 
and then demonstrates the presence of the latter by fuchsin bisulphite. 
One mil of the alcohol to be examined is mixed with 5 mils of potassium 
permanganate 5 per cent and .2-mil sulphuric acid and after two to three 
minutes 1 mil of oxalic acid 8 per cent is added, shaken, and allowed to 
stand until the mixture assumes a yellow tint, then 1 mil, sulphuric acid 
is added. When the solution is completely decolorized 5 mils of fuchsin 
bisulphite solution is introduced and well mixed. After about fifteen 
minutes the violet color appearing in the presence of methyl alcohol 
reaches its maximum intensity. It is claimed that ethyl alcohol increases 
the efficiency of the test. With dilute solutions of methyl alcohol 3 mils 
are mixed with .1 mil ethyl alcohol and 2 mils permanganate 2.5 per cent, 
and the rest of the procedure conducted as outlined above. 

Hinkel's method 2 was credited the most sensitive by Engelhardt and 
Jones, who made a comparative study of all the methods, and is as follows: 
One mil of the sample is placed in a small round-bottomed distilling flask 
and the oxidizing agent added; if ammonium persulphate is used .8 gram 
of the salt is added followed by 3 mils dilute sulphuric acid (1-5), or in 
the case of bichromate 1.5 gram of the salt and 1.5 mil sulphuric acid. In 
either case the mixture is diluted with water to 20 mils and then distilled, 
the distillate being collected in test-tubes in five separate portions of 2 mils 
each. The first two portions may be rejected. To each of the remain- 
ing portions a few drops of .5 per cent solution of morphin are added and 
concentrated sulphuric acid is introduced by means of a pipette so as to 
form a layer at the bottom of the tube. In the presence of formaldehyde 
a violet ring will be found at the junction of the two liquids. 

The Riche and Hardy procedure for detecting and estimating methyl 
alcohol is also recommended if carried out according to the following 
directions : 

The spirituous mixture is distilled, treated with potash, and rectified 
if necessary, to remove an undue amount of water. 

Fifteen grams of coarsely powdered iodin are placed in a small Wurtz 

flask (about 60-mil capacity) connected with a Liebig condenser, and a 

quantity of the distilled spirit equivalent to 10 mils of strength of 60 per 

cent is added. The mixture is well shaken and then 2 grams of red phos- 

1 Compt rend., 150, 529 and 832. 2 Analyst, 1908, 33, 417. 



. HYDROCARBONS— ALCOHOLS— ETHERS 533 

phorus are added. The flask is shaken, connected immediately, allowed to 
stand ten to fifteen minutes with the condenser reversed, placed in a 
beaker or small water-bath which is gradually heated to 100° C. 

The condensed alkyl iodides are collected under water in a graduated 
tube by means of a small adapter attached to the condenser. From 7 to 
9 mils are usually obtained. After the whole of the iodides appear to 
have distilled over, a drop or two of potash solution is added to the water 
in the receiving tube, the whole shaken till colorless, transferred to a 
separator, washed, and finally run into a small flask containing a little 
dry K2CO3. After drying, the iodides are run into a small Wurtz flask 
attached to a short condenser, and having a thermometer in the neck, 
with the bulb opposite the exit tube. The flask is placed on a water- 
bath, which is slowly heated. If the spirit was free from methyl alcohol, 
the iodide will boil about 72° C. and steadily distill at that temperature. 
In the presence of the methyl compound, the initial boiling-point will be 
lower, and a proportion of the iodides will distill under 70° C. 

The iodides are collected in a dry tube, and the first 2| mils are poured 
into a dry flask (75 mils capacity), 2 J mils of aniline are added, the mix- 
ture shaken and gently warmed till it begins to crystallize. It is then set 
aside for twelve hours till the crystallization is complete. 

To the crystalline mass about 50 mils of boiling water are added, and 
the mixture is kept boiling with constant shaking till perfectly clear. It 
is then cooled, a sufficient quantity of strong potash solution added to 
liberate the ethyl methyl aniline oil. By the addition of water it is thrown 
up into the neck of the flask, removed with a pipette, and the flask washed 
and nearly filled with pure water into which the oil is returned, well shaken, 
and thrown up into the neck as before. 

One mil of this oil is then intimately mixed with 10 grams of the follow- 
ing oxidizing mixture placed on a wide test-tube, closed with cotton wool 
and heated for ten or twelve hours at a temperature of 90° C. 

Dry quartz sand 100 grams 

Nitrate of copper 3 grams 

Chloride of sodium 2 grams 

After oxidation the mixture is extracted four times with about 20 mils 
of warm alcohol, filtered into a 100-mil flask, and made up to the mark 
at 15° C. Five mils of alcoholic extract are made up to 100 mils with 
distilled water, and after shaking, 2 mils of this is mixed with 400 mils of 
water in a large beaker. 

Into this 3 feet of white Berlin wool previously boiled in water rendered 
just alkaline, and then well washed in pure water, are placed, and the 
whole warmed to keep it at a temperature not exceeding 75° C. till all 
the color is extracted. The wool should be stirred round occasionally with 
a glass rod. 



534 ORGANIC SUBSTANCES 

The wool after washing and drying will have only a pale reddish-violet 
tint if the alcohol was pure. If methyl alcohol was present the violet is 
much more intense, increasing in depth according to the percentage present 
in the mixture. 

An approximate estimation of the percentage can be made by compar- 
ing the dye given with that from known mixtures treated in the same way. 

In the presence of small quantities of methylated spirit the dyes may 
be somewhat doubtful. In such cases it is necessary to transform a 
larger quantity (30-50 mils) of the purified alcohol into the iodides, and 
then carefully to fractionate the latter by means of a small column of 
glass beads. Each of the first three or four fractions is separately oxidized, 
The methyl compound is largely accumulated in first and second fractions, 
which give a more intense dye than the latter fractions. 

With pure ethyl alcohol there is no appreciable difference in the 
dyes from different fractions. 

Essential oils, camphor, etc., occurring in pharmaceutical preparations 
should be separated from the spirit before preparing the iodides. In the 
case of ether etc., the spirit present would have to be washed out and con- 
centrated. 

Vorisek, 1 in an interesting review On the work done in the matter of 
detecting methyl alcohol, has described a method which is valuable on 
account of its rapidity and because but a very small quantity of material 
is necessary. 
The solutions required include: 

Chromic Acid Solution. — .8 per cent OO3 free of H2SO4. 
Albumen Solutions. — Aldehyde-free milk or the white of one fresh egg 
mixed with 50 mils of clear water filtered and preserved with a few drops 
of chloroform. 

Ferric Chloride Solution. — .4 per cent. 
• Sulphuric Acid. — Free from nitric and nitrous acids. 

Five-tenths to one mil of the sample of alcohol is placed in a 6-inch 
test-tube, 1 mil of the chromic acid solution added, and the liquid diluted 
with water to 4 or 5 mils. Small pieces of pumice are dropped in, the 
test-tube connected with a long air condenser and the liquid distilled into 
another tube by boiling briskly over a small flame. When only about 
.5 mil remains behind in the first test-tube, the condenser is detached and 
rinsed with about 2 mils of water into the receiving test-tube. To the 
distillate are added: 1 drop ferric chloride solution, 2 drops of albumen 
solution, and after mixing 4 to 5 mils of the pure sulphuric acid are poured 
in slowly and carefully. as a layer, generation of much heat being avoided. 
The zone of the contact is then observed, without disturbing the liquids, 
against a white background. A sharply defined violet zone appears almost 
1 J. Soc. Chem. Ind., 1909, 28, 823. 



HYDROCARBONS— ALCOHOLS— ETHERS 



535 



at once if the portion of methyl alcohol is above 5 per cent. With smaller 
amounts but more than 1 per cent the color shows within one minute. 
Several minutes will be required for the color to appear with less than 
1 per cent of methyl alcohol. Pure ethyl alcohol treated in this manner 
gives no color. When organic impurities are present which cannot be 
removed a yellow to reddish color is often obtained, but not violet. 

Albumen in strong solutions gives with concentrated sulphuric acid 
a variety of color reaction. It must not be used in excess and only traces 
of ferric chloride should be added to obtain perfect blank tests. 

Under the conditions here described it was possible to detect as little 
as .001 gram of methyl alcohol in 1 mil of the ethyl compound. 

For determining methyl alcohol, the procedure to be employed for 
obtaining a distillate free from extraneous substances is the same as given 
for ethyl alcohol in the general methods, page 2. The distillate obtained 
in this way may still contain acetone, from which it may be freed by 
conversion into iodoform and the latter removed by shaking out with 
petroleum ether or chloroform, the solvent being washed with saturated 
salt solution and the washings added to the main liquid. The liquid is 
then distilled and the distillate made up to definite volume, and the methyl 
alcohol estimated from the refractive index and the specific gravity accord- 
ing to the tables. 

Doroszewski and Devorzanczyk * state that the values previously 
given in the literature for the refractive index of anhydrous methyl alcohol 
are incorrect. The authors determined the values for pure methyl alcohol 
and its mixtures with water, using the Zeiss immersion refractometer and 
compiled the following table: 



REFRACTIVE INDICES OF MIXTURES OF METHYL ALCOHOL AND 

WATER 



Per Cent of 

Alcohol by 

Weight 


15 
n D 


17.5 
n D 


Per Cent of 

Alcohol by 

Weight 


15 
n D 


17.5 
n D 


100 


1.33057 


1.32957 


40.00 


1.34308 


1.34248 


95.00 


1.33309 


1.33212 


35.02 


1.34235 


1.34180 


90.01 


1.. 33545 


1.33450 


30.02 


1.34138 


1.34091 


85.01 


1 . 33749 


1.33657 


24.98 


1 . 34022 


1 . 33980 


80.00 


1.33925 


1.33835 


20.00 


1.33879 


1.33844 


75.01 


1.34067 


1.33980 


15.01 


1.33730 


1.33702 


69.99 


1.34179 


1.34094 


12.00 


1.33644 


1.33616 


64.99 


1.34272 


1.34192 


10.04 


1.33584 


1.33559 


60.03 


1.34327 


1.34250 


7.04 


1.33504 


1.33480. 


54.99 


1.34365 


1.34290 


5.00 


1.33453 


1.33429 


49.98 


1.34378 


1.34308 


2.00 


1.33384 


1.33362 


45.03 


1.34359 


1.34294 





1.33339 


1.33320 



1 J. Russ Phys. Chem. Ges., 1099, 41, 951; J. S. C. I., 1910, 29, 373, 



536 



ORGANIC SUBSTANCES 



TABLE GIVING THE SPECIFIC GRAVITIES OF AQUEOUS METHYL 
ALCOHOL AT 0° AND 15.56° C. WATER AT 4° = 1000. 



Per Cent 

by Weight 

of 

CHsOH 


Specific 

Gravity 

at 0° 


Specific 
Gravity 
at 15.56° 


1 

Per Cent 

by Weight 

of 

CHsOH 


Specific 

Gravity 

at 0° 


Specific 
Gravity 
at 15.56° 


Per Cent 

by 
Weight of 
HsCOH 


Specific 

Gravity 

at 0° 


Specific 
Gravity 
at 15.56° 





999.87 


999.07 


35 


953.54 


945.67 


70 


886.87 


874.87 


1 


998.06 


997 . 29 


36 


952.04 


943.99 


71 


884.70 


872.62 


2 


996.31 


995.54 


37 


950.51 


942.28 


72 


882.37 


870.21 


3 


994.62 


993.82 


38 


948.95 


940 . 55 


73 


880.03 


867.79 


4 


992 . 99 


992.14 


39 


947.34 


938.77 


74 


877.67 


865.35 


5 


991.42 


990.48 


40 


945.71 


936.97 


75 


875.30 


862.90 


6 


989.90 


988.93 


41 


944.00 


935.10 


76 


872.90 


860.42 


7 


988.43 


987.26 


42 


942.39 


933.35 


77 


870.49 


857.93 


8 


987.01 


985 . 69 


43 


940.76 


931.55 


78 


868.06 


855.42 


9 


985.63 


984.14 


44 


939.11 


929.75 


79 


865.61 


852.90 


10 


984.29 


982 . 62 


45 


937.44 


927.93 


80 


863.14 


850.35 


11 


982.99 


981.11 


46 


935.75 


926.10 


81 


860.66 


847.79 


12 


981.71 


979.62 


47 


934.03 


924.24 


82 


858.16 


845 21 


13 


980.48 


978.14 


48 


932.29 


922.37 


83 


855.64 


842 . 62 


14 


979.26 


976.68 


49 


930.52 


920 . 47 


84 


853.10 


840.01 


15 


978.06 


975.23 


50 


928.73 


918.55 


85 


850 . 55 


837.38 


16 


976.89 


973.79 


51 


926.91 


916.61 


86 


847.98 


834.73 


17 


975.73 


972.35 


52 


925.07 


914.65 


87 


845.39 


832.07 


18 


974.59 


970.93 


53 


923.20 


912.67 


88 


842.78 


829.38 


19 


973.46 


969.50 


54 


921.30 


910.66 


89 


840.15 


826.68 


20 


972.33 


968.08 


55 


919.38 


908.63 


90 


837.51 


823.96 


21 


971.20 


966.66 


56 


917.42 


906.57 


91 


834.85 


821.23 


22 


970.07 


965.24 


57 


915.44 


904.50 


92 


832.18 


818.49 


23 


968.94 


963.81 


58 


913.43 


902.39 


93 


829.48 


815.72 


24 


967.80 


962.38 


59 


911.39 


900.26 


94 


826.77 


812.93 


25 


966.65 


960.93 


60 


909.17 


897.98 


95 


824.04 


810.13 


26 


965.49 


959.49 


61 


907.06 


895.80 


96 


821.29 


807.31 


27 


964.30 


958.02 


62 


904.92 


893.58 


97 


818.53 


804.48 


28 


963 . 10 


956.55 


63 


902.76 


891.33 


98 * 


815.76 


801.64 


29 


961.87 


955.06 


64 


900 . 56 


889.05 


99 


812.95 


798.76 


30 


960.57 


953.55 


65 


898.35 


886.76 


100 


810.15 


795.89 


31 


959.21 


952.11 


66 


896.11 


884.43 








. 32 


957.83 


950.53 


67 


893.84 


882.02 








33 


956.43 


948.94 


68 


891.54 


879.70 








34 


955.00 


947.32 


69 


889.22 


877.14 









HYDROCARBONS— ALCOHOLS— ETHERS 537 

Ethyl Alcohol 

Ethyl alcohol has such an extensive use in medicinal preparations that 
dilation on this point would be superfluous. As a drug pure and simple it 
is employed mainly by the practitioner in individual cases, and hence in 
general it functionates as a vehicle and solvent, and not as a drug. Never- 
theless, under the Food and Drugs Act it falls in the class of inhibited 
articles that must be declared in exact terms on the label, and in the specific 
clause where it is mentioned there is no Hmitations as to its use whether 
it be as a remedy itself, or simply as a vehicle or solvent in the same class 
as water or glycerin. 

The alcohol of commerce includes absolute alcohol, which contains 
not more than 1 per cent by weight of water. Cologne spirits, or U. S. P. 
Alcohol, 94.9 per cent by volume and 92.3 per cent by weight; alcohol 
94 per cent by volume, used in large amounts for commercial purposes, 
dilute alcohol 48.9 per cent by volume and 41.5 per cent by weight, and 
denatured alcohol. 

The grade of alcohol which has the greatest use is the 94 per cent 
product. In regulation 28 for the enforcement of the Food and Drugs 
Act, it states in paragraph (A) that " The term ' alcohol ' is defined to 
mean common or ethyl alcohol," and in regulation 30 that "the expression 
of 'quantity' or 'proportion' shall mean the average percentage by volume 
in the finished product." Now while it is well known to a chemist that 
the percentage of alcohol is always given in terms of absolute alcohol and 
that the statement " common or ethyl alcohol " refers to the chemical com- 
position of the alcohol and not to the commercial grade, the term used 
in the regulation furnishes an excellent subject for legal quibbling where 
there is a conflict of testimony over the quantity of alcohol present in a 
mixture. This should be borne in mind by any analyst who is concerned 
in a case involving the question of alcoholic percentage, and be fully 
explained to the attorney before the evidence is introduced in order that 
the latter may be prepared for proper interrogatory. 

Pure ethyl alcohol is a transparent, colorless, very limpid liquid, inflam- 
mable, of a pleasant spirituous odor and burning taste, has a specific gravity 
of .797 at 15.6°, boils about 78°, solidifies below -30°, and is miscible in all 
proportions with water, ether, and chloroform. It resembles methyl alco- 
hol in chemical properties, forming ethylates with sodium and potassium, 
which are readily decomposed by water, combining with acids to form 
ethereal salts, and forming halogen compounds with phosphorus halides. 
On oxidation it is converted to acetaldehyde and acetic acid. It gives 
the iodoform reaction with iodin and alkali and this reaction is commonly 
used to demonstrate its presence, though many other substances, includ- 
ing acetone and acetaldehyde, will give the same test. The lactic acids 



538 ORGANIC SUBSTANCES 

give it, and /3-hydroxybutyric, quercitol, inositol, pyruvic acid, and aldol 
all give precipitates having a characteristic odor, though they may con- 
sist of homologues or substitued derivatives of iodoform. 

The detection of ethyl alcohol can be accomplished in a distillate from 
the product under investigation. If there is reason to suspect the pres- 
ece of ether, chloroform, volatile oil, or other material soluble in petroleum 
ether, the distillate must be diluted, saturated with sodium chloride, and 
shaken out two or three times with petroleum ether of low boiling-point. 
The solvent is washed with saturated sodium chloride solution, which is 
returned to the main liquid and the latter redistilled and the neutrality 
of the distillate assured. 

The presence of ethyl alcohol may be established by the formation of 
ethyl acetate, when the sample is warmed with an acetate and sulphuric 
acid. 

With iodin and an alkali acetone yields iodoform in the cold. With 
the same reagents alcohol yields iodoform at 70° C. 

To 2 or 3 mils of the distillate add 2 or 3 drops of 1 per cent solution 
of sodium nitroprusside, and then 2 or 3 drops of 10 per cent solution of 
sodium hydroxide. Divide into 2 portions, a and b. To h add 3 to 5 
drops of glacial acetic acid. In the presence of as much as 1 or 2 per cent 
of acetone a is at first orange or yellow-orange colored, changing after 
twenty minutes to a clear yellow; b is at first red when viewed against a 
white background, the hue being unchanged after twenty minutes, although 
the intensity decreases so that in the case of solutions containing as little 
as 1 per cent of acetone the color is so pale as to be barely distinguishable. 

To 10 mils of the distillate add 1 gram solid KOH, and without waiting 
for this to dissolve add 10 drops salicylaldehyde and warm the whole at 
70°. In the presence of acetone a purple-red contact ring develops; or, 
if the hydroxide is all dissolved before the addition of the salicylaldehyde, 
the liquid becomes 3 T ellow, then reddish, and finally purple-red. 

Appreciable quantities of aldehyde will be detected by the odor, and 
small amounts by the pink color, which develops on adding fuchsin 
decolorized by sulphurous acid, though it may be here noted that almost 
any alcoholic distillate will give a test for aldehyde. 

Methyl alcohol may be detected by the tests described under that 
substance. 

The determination of ethyl alcohol in medicinal preparations has been 
described on page 2 under the general methods. 

When the distillate contains both methyl and ethyl alcohol the percent- 
ages of each can be ascertained by the method and tables of Leach and 
Lythgoe. In using this method the worker should always assure him- 
self by previous qualitative test that his distillate contains methyl alcohol, 
and that it is free from essential oils and other substances having refrac- 



HYDROCARBONS— ALCOHOLS— ETHERS 539 

tive indices. Unless this is done he may be subjected to much embarrass- 
ment by reporting a percentage of methyl alcohol and finding out too 
late that none is present. The writer in checking over the work of other 
men has more than once saved an overzealous chemist the chagrin of 
having to refute his analysis in contest when he had erroneously reported 
a definite percentage of methyl alcohol without making a qualitative test. 

Determine at 20° C. the refraction of the distillate obtained in the 
determination of alcohol by the immersion refract ometer. If on reference 
to the table the refraction shows the percentage of alcohol agreeing with 
that obtained from the specific gravity, it may safely be assumed that no 
methyl alcohol is present. If, however, there is an appreciable amount 
of methyl alcohol the low refractometer reading will at once indicate the 
fact. If the absence from the solution of other refractive substances than 
water and the alcohols is assured, this qualitative test by difference in 
refraction is conclusive. 

The addition of methyl alcohol decreases the refraction in direct pro- 
portion to the amount present; hence the quantitative calculation is 
readily made by interpolation in the table on page 540, using the figures for 
pure ethyl and methyl alcohol of the same alcoholic strength as the sample. 

A rapid method for Determining Alcohol and Ether in Mixtures of 
both has been devised by Julius Fleisher and Heinrich Frank. 1 

This method depends on the fact that when a mixture of ether, alcohol 
and water is treated with benzin, two distinct layers are formed, the 
benzin taking up the ether while the volume increase of the water added 
gives the alcoholic content. 

Ten mils of the mixture of alcohol and ether are mixed with 5 mils 
benzin and 5 mils water in a glass cylinder. After a few minutes a sharp 
separation takes place and two layers are formed. The increase in vol- 
ume of benzin and water layers gives the proportion of alcohol and ether. 

In a mixture of alcohol, ether, and water, the specific gravity of the 
three is first determined, then the volume of ether as above. With these 
data the alcohol can readily be determined by the following formula 

where & = the sp. gr. of the alcohol and water; 

d = ihe sp. gr. of the ether alcohol mixture; 
a = number of mils ether; .729 sp. gr. of ether. 
From S the alcohol can be calculated in the usual manner. 
Example: Sp. gr. of mixture, .880. 

Increase in benzin, 2 cm. 

c 8.800- (2 X. 729 ) ' . 

S = -^ — ^ -=• 917 = 58 per cent alcohol. 

1 Apoth. Zeit. No. 55, 1907, page 579. 



540 



ORGANIC SUBSTANCES 



Scale readings of the Zeiss immersion refractometer at 20° C, corresponding to each 
per cent by weight of methyl and ethyl alcohols 



Per Cent 


Scale Readings 


Per Cent 
Alcohol 

by 
Weight 


Scale Readings 


1 

Per Cent 
Alcohol 

by 
Weight 


Scale Readings 


Alcohol 

by 
Weight 


Methyl 
Alcohol 


Ethyl 
Alcohol 


Methyl 
Alcohol 


Ethyl 
Alcohol 


Methyl 
Alcohol 


i 

Ethyl 
Alcohol 





14.5 


14.5 


35 


35.8 


75.8 


70 


33.0 


100.0 


1 


14.8 


16.0 


36 


36.3 


76.9 


71 


32.3 


100.2 


2 


15.4 


17.6 


37 


36.8 


78.0 


72 


31.7 


100.4 


3 


16.0 


19.1 


38 


37.3 


79.1 


73 


31.1 


100.6 


4 


16.6 


20.7 


39 


37.7 


80.2 


74 


30.4 


100.8 


5 


17.2 


22.3 


40 


38.1 


81.3 


75 


29.7 


101.0 


6 


17.8 


24.1 


41 


38.4 


82.3 


76 


29.0 


101.0 


7 


18.4 


25.9 


42 


38.8 


83.3 


77 


28.3 


100.9 


8 


19.0 


27.8 


43 


39.2 


84.2 


78 


27.6 


100.9 


9 


19.6 


29.6 


44 


39.3 


85.2 


79 


26.8 


100.8 


10 


20.2 


31.4 


45 


39.4 


86.2 


80 


26.0 


100.7 


11 


20.8 


33.2 


46 


39.5 


87.0 


81 


25.1 


100.6 


12 


21 4 


35.0 


47 


39.6 


87.8 


82 


24.3 


100.5 


13 


22.0 


36.9 


48 


39.7 


88.7 


83 


23.6 


100.4 


14 


22.6 


38.7 


49 


39.8 


89.5 


84 


22.8 


100.3 


15 


23.2 


4a: 5 


50 


39.8 


90.3 


85 


21.8 


100.1 


16 


23.9 


42.5 


51 


39.7 


91.1 


86 


20.8 


99.8 


17 


24.5 


44.5 


52 


39.6 


91.8 


87 


19.7 


99.5 


18 


25.2 


46.5 


53 


39.6 


92.4 


88 


18.6 


99.2 


19 


25.8 


48.5 


54 


-39.5 


93.0 


89 


17.3 


98.9 


20 


26.5 


50.5 


55 


39.4 


93.6 


90 


16.1 


98.6 


21 


27.1 


52.4 


56 


39.2 


94.1 


91 


14.9 


98.3 


22 


27.8 


54.3 


57 


39.0 


94.7 


92 


13.7 


97.8 


23 


28.4 


56.3 


58 


38.6 


95.2 


93 


12.4 


97.2 


24 


29.1 


58.2 


59 


38.3 


95.7 


94 


11.0 


96.4 


25 


29.7 


60.1 


60 


37.9 


96.2 


95 


9.6 


95.7 


26 


30.3 


61.9 


61 


37.5 


96.7 


96 


8.2 


94.9 


27 


30.9 


63.7 


62 


37.0 


97.1 


97 


6.7 


94.0 


28 


31.6 


65.5 


63 


36.5 


97.5 


98 


3.5 


93.0 


29 


32.2 


67.2 


64 


36.0 


98.0 


99 


3.5 


92.0 


30 


32.8 


69.0 


65 


35.5 


98.3 


100 


2.0 


91.0 


31 


33.5 


70.4 


66 


35.0 


98.7 








32 


34.1 


71.7 


67 


34.5 


99.1 








33 


34.7 


73.1 


68 


34.0 


99.4 








34 


35.2 


74.4 


69 


33.5 


99.7 









HYDROCARBONS— ALCOHOLS— ETHERS 541 



METHOD FOR ESTIMATING ALCOHOL IN THE PRESENCE OF 
CARBOLIC ACID 

The following procedure is described by J. Erlich. 1 

Pipette 50 mils of sample into a 300-mil flask containing 30 mils water, 
made strongly alkaline with an excess of strong NaOH solution, so that 
the final volume is about 100 mils and the odor of phenol is absent. Add 
glass beads and distill into a 50-mil graduated flask containing 1 or 2 mils 
water. The end of the condenser or adapter should almost touch the sur- 
face of the distillate in the receiver, especially at the beginning of a dis- 
tillation. A drawn-out thistle tube is serviceable in this connection. The 
flask is lowered as distillation proceeds. 

When nearly 50 mils of distillate have been collected, remove the 
receiver, dilute with water to mark, shake thoroughly and pipette 25 mils 
into another 300-mil flask containing 30 mils water. 

Precipitate the phenol as its tribromderivative by adding bromin 
water, drop by drop, to slight excess while rotating flask. Without delay 
add normal " hypo " solution (a few drops will be sufficient to decolorize; 
i.e., to remove the free bromin excess), and finally add enough strong 
NaOH solution to dissolve the white tribromphenol as its phenate, and 
then a decided excess of alkali. The final volume will be less than 100 mils. 
After the addition of glass beads distill into the 50-mil flask as before, 
dilute to mark and determine density by weighing. The percentage of 
alcohol in this last distillate multiplied by two gives the required figure. 

For higher concentration of alcohol a 100-mil receiving flask may be 
substituted in the above method, and 50 mils of the distillate treated and 
redistilled. For high concentrations of phenol the method is directly 
applicable, since the amount of phenol which passes over during the first 
distillation is small. If the original phenol content is low, the first dis- 
tillation may be omitted. In this case the 50-mil sample plus 30 mils 
water in the 300-mil flask is treated directly with the bromin water to 
slight excess as shown by color; then add " hypo," alkali, etc., as above 
and distill into 50 or 100-mil flask according to alcohol concentration. 
Samples high in phenol cannot be treated in this manner, because the 
bulky precipitate of tribromphenol prevents thorough mixing while adding 
the bromin water, making it impossible to perceive when an excess of 
bromin is present. 

The hydrobromic acid formed by the action of bromin on the phenol 
is neutralized and retained by the alkali. 

1 J. Ind. and Eng. Chem., 1916, 8, 240. 



542 ORGANIC SUBSTANCES 



PROPYL AND BUTYL ALCOHOLS 



None of the isomers of those two alcohols by themselves are of any 
importance in medicinal chemistry. Propaesin, one of the newer anes- 
thetics, which is the propyl ester of paramido-benzoic acid, would prob- 
ably, under proper conditions of hydrolysis, yield propyl alcohol, and there 
are several ethereal salts with the propyl and butyl radicles which might 
occasionally require identification. Chloretone or acetone-chloroform is a 
place derivative of tertiary butyl alcohol, and has quite an extensive use 
as an anesthetic and hypnotic. 

TRIHYDRIC AND POLYHYDRIC ALCOHOLS 

Glycerol 

The simplest trihydric alcohol is glycerol, C3H 5 (OH)3. This sub- 
stance has a wide use in the preparation of medicines, though as a drug 
itself its employment is limited. It occurs as a preservative, a vehicle, 
and a solvent in liquid preparations, and takes part in many external 
remedies as an emollient, as a lubricant in suppositories, and as a laxative. 
Commercial glycerin is a thick syrup containing about 95 per cent of pure 
glycerol, and is chiefly obtained from the residues in the manufacture of 
soap. Of late years the demand for a pure article has been so rigid and 
the improvements in manufacture so rapid, that it is a simple matter to 
obtain a product of the highest refinement. 

Glycerin is a component of many liquid drug extracts which are used 
in the formulas of complex preparations, and its identification often serves 
indirectly to substantiate the presence of these drugs. 

Pure glycerol is a colorless, crystalline substance, melting 17°, but it 
does not solidify readily, owing to the presence of water, which it absorbs 
with great avidity from the air up to 50 per cent. When pure it boils at 
290° without decomposition. It mixes in all proportions with alcohol 
and water, but is slightly soluble in ether, and is insoluble in petroleum 
ether. It has a sweet taste. It loses weight gradually when heated at 
the temperature of the water-bath. When heated with dehydrating agents, 
potassium hydrogen sulphate, sulphuric acid, or phosphorus pentoxide, 
it is decomposed into acrolein and water, the former readily recognized 
by its disagreeable odor and irritating effect on the mucous membrane. 
On careful oxidation it yields glyceric acid, CH 2 OHCHOHCOOH, but 
usually a mixture of oxalic, gly colic, and carbonic acids results. It forms 
mono-, di-, and tri-esters with acids, the derivatives obtained with hydro- 
chloric acid are called chlorhydrins. The trinitrate, known as nitro- 
glycerin, is a very important medicinal agent, and the glycerophosphates 
have an extensive use 



HYDROCARBONS— ALCOHOLS— ETHERS 543 

The writer, with L. F. Kebler, had occasion to make a critical survey 
of the glycerin produced by all of the different manufacturers in this 
country and of the imported products. 

The claim had often been advanced that the present glycerin stand- 
ard is too rigid and in certain respects can rarely be attained; hence the 
Pharmacopoeia should be so modified that it will be consistent with con- 
ditions which actually exist. To confirm or refute this statement it was 
necessary to investigate the quality of the glycerin on the market in the 
United States, and to determine exactly to what extent samples from 
different sources conform to the tests prescribed in the Pharmacopoeia. 
Another purpose was to learn whether there were any glycerins which 
would not reduce Fehling's solution, the claim that no such article was 
obtainable being of importance owing to the use of glycerin in the 
preparation of Haines's solution, an alkaline copper liquid which has been 
recommended for detecting sugar in urine and whose value as a testing 
reagent would naturally be impared if reduction occurred when no sugar 
was present. 

The samples were examined first according to the methods prescribed 
in the Pharmacopoeia. A rigid examination was made for arsenic in 
order to determine whether even traces of this substance were left in the 
glycerin; special tests were made to note the action of Fehling's solu- 
tion, and a sample of Haines's solution was made up with each product. 
The physical appearance was good in every instance. The samples were 
all neutral to litmus paper. The specific gravities at 25° C. varied from 
1.248 to 1.258, in most cases being above 1.250, with an average of 
1.254. In this respect they were all above the standard requirement of 
1.246 at 25° C. 

The pharmacopceial test for sugar gave negative results, as would 
be expected. Experiments were then conducted noting the action of 
Fehling's solution, using concentrated and diluted glycerin and without 
previously heating with acid as in performing the sugar test. Two samples 
which reduced Fehling's solution in the undiluted state gave no reduction 
on dilution; two reduced the solution on diluting, but did not in the con- 
centrated condition ; three showed no reduction either diluted or undiluted ; 
while the remainder reduced Fehling's solution under any condition. 
Several of the samples which reduced Fehling's solution in the undiluted 
condition had reduced ammoniacal silver nitrate in the Hager test. 1 
Haines's solution when made according to directions given in works on 
urinalysis 2 was reduced in every instance, thereby substantiating the 
claims which had already been advanced in this connection. 3 

1 Handbuch der Pharm. Praxis, 4th ed., 1905, 1 : 1221. 

2 Purdy, R. G., Practical Urinalysis and Urinary Diagnosis, 1895, page 103. 

3 Mayer, J. L., The Reducing Action of Glycerin, Merck's Report, 1905, 14 : 165. 



544 ORGANIC SUBSTANCES 

Most of the samples were well within the requirements as to the color 
imparted by concentrated sulphuric acid, various shades of yellow occur- 
ring. One sample was dark brown and fluorescent, while another turned 
brown and gave off a strong fatty odor. In fact, the odor varied more 
than the color, some samples having the fatty odor just mentioned, while 
others had an unmistakably pleasant aromatic smell; four had a character- 
istic hydrocarbon odor, and in one instance the product was practically 
without color or odor, but evolved a quantity of minute gas bubbles. 
When the samples were treated with alcohol and sulphuric acid and 
warmed on the steam-bath ethereal odors were noted in all cases, the 
unpleasant butyric ester predominating, although with two samples an 
agreeable fruity odor was noticed. In certain instances this test ran parallel 
with the former one, in that samples which gave scarcely any color or 
odor with sulphuric acid gave but a slight ethereal odor, but for the most 
part these tests were entirely at variance. When simply heated on the 
steam-bath marked differences in odor were noted, four samples gave off 
a slight odor of no particular character, two an aromatic odor, and the 
remainder a fatty odor of varying intensity. 

A reaction was obtained showing a slight trace of sulphates in five 
products, a trace of chloride in two, and a reduction of silver nitrate in 
five, this being very marked with one specimen; oxalates were indicated 
in two samples from the same manufacturer; heavy metals were shown 
in three cases, while six gave no reactions for metals or acids. 

Only one sample showed the presence of objectionable amounts of 
arsenic, and this was of foreign make and labeled " arsenic free." The 
Marsh test was rigidly applied to every glycerin in order to determine 
how completely the arsenic had been eliminated, six specimens gave no 
mirror, and the others, with the exception of the one above mentioned, 
contained less than one part in a million. It is of interest to note that 
of two samples submitted by one manufacturer one contained arsenic and 
the other did not. 

Satisfactory results seemed impossible with the pharmacopceial test 
using ammoniacal silver nitrate; reduction took place in every instance, 
and it was apparent that no significant conclusions could be drawn from 
its use. Accordingly it was abandoned for the test described by Hager, 1 
with which better comparative results were obtained. Five mils of the 
sample were mixed with 5 mils of 26 per cent ammonia water and 5 drops 
of silver nitrate added; the mixture was allowed to stand at the ordinary 
temperature in the dark for fifteen minutes and its appearance noted. 
There was no reduction of the silver nitrate in six cases, and a marked 
reduction in two, the other samples being slightly colored. 

The investigation showed that glycerin could be produced which would 

1 Loc. cit. 



HYDROCARBONS— ALCOHOLS— ETHERS 545 

answer all of the pharmacopoeial requirements with the exception of the 
ammoniacal silver nitrate test. It also showed that although some 
glycerins gave off a fruity odor when treated with alcohol and sulphuric 
acid, they were otherwise of good quality; therefore the wording of this 
test should be modified in order to include the disagreeable butyric odor 
as it now discriminates only against a " Fruity odor." 

It appeared from this investigation that a high-grade glycerin should 
meet the following requirements: 

Its specific gravity should be about 1.250 at 25° C. 

It should be neutral to litmus paper. 

It should leave no ash on ignition. 

It should give off but a slight odor when heated alone at the temper- 
ature of the water-bath. 

It should not give off an unpleasant ethereal odor nor a strong fruity 
odor when warmed with alcohol and sulphuric acid. 

It should not develop more than a yellow color when mixed with an 
equal volume of sulphuric acid and no disagreeable odor should be evolved. 

When treated with silver nitrate and ammonium hydroxide, accord- 
ing to Hager, no color, or at most only a yellow color, should develop. 

It should give no reaction for sulphates, chlorides, oxalates, or metals. 

It should give no reaction for sugars. 

When diluted with an equal volume of water it should give no reduction 
with Fehling's solution. 

It should not contain arsenic in excess of the Kmit prescribed in the 
Pharmacopoeia. 

IDENTIFICATION OF GLYCERIN 

The question of the detection and determination of glycerin in mixtures 
may or may not be of great importance in our work. Its detection is simple 
in any case and its accurate estimation is not of moment, except were the 
analyst desires to bring the percentage of a mixture up to 100. But it 
might as well be emphasized at this point that in our present state of 
knowledge, the accurate estimation of glycerin is difficult in complex 
mixtures of this kind. In the residues from soap stocks the glycerin may 
be determined by the " acetin " method, and in some medicinal mixtures 
it might be possible to arrive at the amount of glycerin by the same pro- 
cedure after removing interfering substances. But usually the evapor- 
ations and precipitations cause such losses that any determination is of 
little value. 

The presence of glycerin in a mixture is first apparent in running an 
ash determination, for as soon as a sufficient condensation has been reached 
and the mass has taken fire, little sky-rocket evolutions become apparent, 



546 ORGANIC SUBSTANCES 

which fly off in parabolic curves, sometimes twisting like serpents and 
leaving trails of white smoke. 

In the general scheme of the qualitative analysis outlined in my work 
on that subject, glycerin will remain in the aqueous solution through both 
the acid and alkaline shake-out, and then can be purified, and identified 
by the following reactions: 

Mullikin's Reaction. — The residue suspected to be glycerin and which 
has been purified by the lime-alcohol ether treatment (see below) should 
be made up with water to a dilution of about 1 per cent. Add 5 drops 
1 per cent solution pyrogallic acid, then 3 mils cone, sulphuric acid. 
Shake and heat to boiling and boil for about half a minute. If glycerin 
is present a purple color will begin to develop, deepening as the boiling 
is continued. Cool and add about 20 mils alcohol when the purple color 
shows to advantage. 

Mandel and Neuberg have worked out a method for detecting glycerin 
by converting it to glycerose, which is then identified by the" orcin reaction. 
About 2 mils of the glycerin solution are mixed with normal sodium hypo- 
chlorite solution and the mixture boiled for one minute. The addition 
of hypochlorite and boiling are repeated, the hot solution treated with 
three drops of hydrochloric acid (1.124), boiled from thirty to sixty seconds, 
or until the chlorin is expelled and a perfectly colorless solution obtained. 
The liquid is mixed with an equal volume of fuming hydrochloric acid 
and a few crystals of orcin and boiled again, when in the presence of 
glycerin a violet or greenish blue coloration will be produced. 

Pentoses give the same reaction, but they also reduce Fehling's solu- 
tion, which glycerin does not. 

Sensitive reactions for the detection and identification of glycerin have 
been described by L. Deniges. 1 

By transforming glycerin with the aid of halogens into dioxyacetone 
and utilizing the color reactions of this product as well as other properties 
it is possible to identify glycerin, even when present only in traces. The 
transformation can be effected either with chlorin or bromin water. 
The latter being easier obtainable is also preferable. 

Put into a test-tube .08 to .1 gram of glycerin or 1 mil of 10 per cent 
solution of glycerin and add 10 mils bromine water, freshly prepared by 
shaking vigorously 100 mils of distilled water with .3 mil of bromine in 
a flask of a capacity of 200 to 250 mils. The shaking should be continued 
until all bromin is dissolved. The test-tube is then heated on the water- 
bath for about twenty minutes, and brought to boiling until all bromine 
has disappeared, then cooled. The mixture, which for convenience shall 
be called G, is then subjected to the following tests: 

1 Compt, rend., 148, 570, 572. 



HYDROCARBONS— ALCOHOLS— ETHERS 547 



A — Colorimeter 

1. Direct Reactions. — Put into four test-tubes .1 mil of an alcoholic solu- 
tion of the following substances: 

A 5 per cent solution of codein. 

A 5 per cent solution of resorcinol. 

A 5 per cent solution of thymol. 

A 2 per cent solution of beta-naphthol. 
To the test-tube with codein add .2 mil of G and 2 mils of water. Into 
the other three tubes put .4 mil of G but no water. To each tube add 
2 mils of H2SO4 (sp. gr. 1.84) ; shake and heat only the first and last tubes 
for two minutes on the boiling water-bath. After about two minutes 
the following may be observed: A beautiful greenish-blue color and a 
strong absorption band in red in the tube with codein: an emerald-green 
color and a greenish flourescence in the tube with /3-naphthol, also two 
absorption bands in the green and red spectrum: a blood-red color in 
the tube with resorcinol, which becomes reddish yellow or yellow on suf- 
ficient dilution with acetic or sulphuric acid, two absorption bands in 
blue and yellow spectrum; in the tube with thymol a wine red color, 
changing to rose on dilution. 

2. Reactions in Presence of Potassium Bromide. — Put into two test- 
tubes .1 mil of a 4 per cent potassium bromide solution, .4 mil of G, then 
. 1 mil of a 5 per cent alcoholic solution of salicylic acid into one tube, and 
add an equal quantity of an equally strong solution of guaiacol into the 
other. Add to each 2 mils of H2SO4 (1.84) and heat for two minutes on 
the water-bath. The tube with salicylic acid will then show an intense 
violet-red coloration, also two absorption bands in yellow and blue. (Very 
sensitive and characteristic reaction.) The tube with guaiacol shows an 
intense blue tinge and an absorptive band in red. 

Before attempting to identify glycerin in complex mixtures, it should 
be separated as completely as possible from the other constituents. The 
same precaution should be taken in the case of a quantitative estimation. 

When working with the liquid preparations, the samples should be con- 
centrated after the addition of a considerable quantity of milk of lime, 
and the residue extracted several times with absolute alcohol. The com- 
bined alcoholic extracts are filtered and treated with 1| times the volume 
of absolute ether. After the precipitate has settled, the clear liquid is 
filtered off, the filter washed with an alcohol-ether mixture of the same 
proportion as that used for precipitating, and then allowed to evaporate 
at a moderate temperature. In some instances it will be advantageous 
to repeat the entire operation, or at least the solution in alcohol and 
precipitation with ether, using smaller quantities of the reagents. 

The glycerin in cold creams and dentifrices can usually be separated 



548 



ORGANIC SUBSTANCES 



by warming the sample, when the soap and other solid constituents will 
separate out from the liquid portion. 

Estimation of Glycerin. — The amount of glycerin in a mixture of pure 
glycerin and water may be readily determined from the specific gravity 
of the mixture and referring to the table. 

SPECIFIC GRAVITY OF GLYCERIN AND WATER MIXTURES 



Per Cent 
Glycerin 


Sp. Gr. at 
15°C. =59°F. 


Per Cent 
Glycerin 


Sp. Gr. at 
15°C. =59°F. 


Per Cent 
Glycerin 


Sp. Gr. at 
15°C. =59°F. 


Per Cent 
Glycerin 


Sp. Gr. at 
15°C. =59°F. 


1 


1.00236 


26 


1.06500 


51 


1 . 13265 


76 


1.20131 


2 


1.00473 


27 


1.06765 


52 


1 . 13539 


77 


1.20404 


3 


1.00711 


28 


1.07031 


53 


1 . 13814 


78 


1.20677 


4 


1.00949 


29 


1.07297 


54 


1 . 14088 


79 


1.20949 


5 


1.01189 


30 


1.07564 


55 


1.14362 


80 


1.21221 


6 


1.01430 


31 


1.07832 


56 


1.14637 


81 


1.21493 


7 


1.01673 


32 


1.08100 


57 


1 . 14912 


82 


1.21766 


8 


1.01917 


33 


1.08370 


58 


1 . 15187 


83 


1.22038 


9 


1.02163 


34 


1.08639 


59 


1.15462 


84 


1.22310 


10 


1.02409 


35 


1.08908 


60 


1 . 15737 


85 


1.22583 


11 


1.02656 


36 


1.09176 


61 


1.16011 


86 


1.22855 


12 


1 . 02904 


37 


1.09445 


62 


1 . 16286 


87 


1.23128 


13 


1.03153 


38 


1.09713 


63 


1 . 16561 


88 


1.23400 


14 


1.03403 


39 


1.09983 


64 


1 . 16837 


89 


1.23673 


15 


1.03653 


40 


1.10253 


65 


1.17113 


90 


1.23945 


16 


1.03905 


41 


1 . 10525 


66 


1 . 17387 


91 


1.24217 


17 


1.04160 


42 


1 . 10798 


67 


1 . 17662 


92 


1.24487 


18 


1.04416 


43 


1.11071 


68 


1.17937 


93 


1.24756 


19 


1.04672 


44 


1 . 11345 


69 


1 . 18212 


94 


1.25021 


20 


1.04930 


45 


1.11618 


70 


1.18487 


95 


1.25285 


21 


1.05189 


46 


1.11893 


71 


1.18761 


96 


1.25547 


22 


1.05449 


47 


1.12167 


72 


1 . 19035 


97 


1.25809 


23 


1.05712 


48 


1 . 12441 


73 


1 . 19309 


98 


1.26072 


24 


1.05973 


49 


1.12716 


74 


1 . 19583 


99 


1.26335 


25 


1.06236 


50 


1 . 12990 


75 


1 . 19857 


100 


1 . 26596 



Determination of Glycerin in Meat Juices and Extracts. F. C. 
Cook. 1 — Acetone Extraction Method. — Weigh approximately 2 grams of a 
solid or 5 grams of a liquid meat preparation in a small lead dish contain- 
ing 20 grams of ignited sand. Transfer the lead dish and its contents to 
mortar containing more ignited sand and several grams of anhydrous 
sodium sulphate and mix thoroughly. Transfer the lead dish and the sand 
to a Soxhlet apparatus which has a piece of cotton placed in the side arm 
to prevent the siphoning over of sand, etc. Extract the entire mass with 

1 J. Assoc. Off. Agri. Chem., 1915, 1, 279. 



HYDROCARBONS— ALCOHOLS— ETHERS 549 

redistilled anhydrous acetone for ten hours; distill the acetone, carefully 
removing the last trace by means of a vacuum pump; take up the glycerin 
in water, add a little silver nitrate, make to 100 mils volume, let stand 
overnight, filter, and oxidize a portion of the nitrate according to the 
dichromate method of Hehner. 

Hehner's Dichromate Method for Glycerol. — One part of glycerol is 
quantitatively oxidized to carbonic acid by 7.486 parts of dichromate in 
the presence of sulphuric acid. The solutions required are : 

Standard Potassium Dichromate. — 74.86 grams of pure potassium 
dichromate are dissolved in water, 150 mils of concentrated sulphuric acid 
added, and when cold, diluted to a liter. One mil = .01 gram glycerol. 

A weaker solution is also made by diluting 100 mils of the strong 
solution to a liter. 

These solutions should be controlled by a ferrous solution of known 
strength, if there is any doubt about the purity of the dichromate. 

Solution of Double Iron Salt. — 240 grams of ferrous ammonium sul- 
phate are dissolved with 50 mils of concentrated sulphuric acid to a liter, 
and its relation to the standard dichromate must be accurately found 
from time to time by titration with the latter, using the ferricyanide 
indicator. 

Method of Procedure. — With concentrated or tolerably pure samples of 
glycerin it is only necessary to take a small weighed portion, say 0.2 gram 
or so, dilute moderately, add 10 or 15 mils of concentrated sulphuric acid 
and 30 or 40 mils of the stronger dichromate, place the beaker covered 
with a watch-glass in a water-bath and digest for two hours; the excess 
of dichromate is then found by titration with the standard iron solution. 
The weaker dichromate is useful in completing the titration where accuracy 
is required. As the stronger dichromate and the iron solution are both 
concentrated, they must be used at a temperature as near 15° C. as pos- 
sible. If the operation be carried out on a water-bath and kept at normal 
temperature during the operation no correction will be necessary. In 
the case of crude glycerin it must be purified from chlorin or aldehyde 
compounds as follows: About 1.5 grams of the diluted sample is placed 
in a 100-mil flask, some moist silver oxide added, and allowed to stand 
ten minutes. Basic lead acetate is then added in slight excess, the meas- 
ure made up to 100 mils, filtered through a dry filter, and 25 mils or so 
digested with excess of dichromate, and titrated as before described. 

Determination of Glycerin in Pharmaceutical Preparations. — If the 
sample is a paste, cream or emollient, weigh out 10 grams, add water and 
bring to a uniform mixture, and then transfer to a 500-mil graduated flask, 
render slightly acid with hydrochloric acid, and make up to the mark. 

With the liquid products use a sample of 10-50 mils, depending on 
the concentration. 



550 ORGANIC SUBSTANCES 

Filter off 100-mil aliquots, concentrate to about 15 mils, add 5-10 
grams of clean uniform sea sand, 5-10 mils of milk of lime (containing 
about 15 per cent CaO) and evaporate to pastry consistency. Treat the 
moist residue with 50 mils of 90 per cent alcohol (by volume) remove the 
substance adhering to the sides of the dish with a spatula and rub the 
whole mass to a paste. Heat the mixture on a water-bath to incipient 
boiling, stirring constantly, and decant the liquid through a filter into an 
evaporating dish. Wash the residue by decantation, with 10-mil portions 
of hot 90 per cent alcohol, until the filtrate amounts to 150 mils. Evapo- 
rate the filtrate to syrupy consistency at a temperature below the boiling- 
point of water; transfer the residue to a small glass-stoppered, graduated 
cylinder with 20 mils of absolute alcohol and add three portions of 10 mils 
each of anhydrous ether, shaking after each addition. Let stand until 
clear, then pour off through a dry filter, wash cylinder and filter with a 
mixture of one part absolute alcohol and 1| parts of anhydrous ether. 
Evaporate the filtrate to syrupy consistency and immediately remove 
from warm bath. 

Dissolve in water, transfer to a larger beaker and add enough water 
to measure about 400 mils. Add 10 grams potassium hydroxide and an 
excess of potassium permanganate either in the form of a saturated solu- 
tion or as crystals. An excess is present when the liquid is no longer 
green, but shows a bluish or magenta color. Boil one hour, then add 
drop by drop a saturated solution of sodium sulphite until solution is 
just decolorized. Transfer contents of beaker to a 500-mil graduated 
flask, washing out with hot water, and making up to 515 mils to allow 
for the hot water and precipitate. Filter hot through a dry filter, leaving 
precipitate unwashed, and cool to room temperature; 400 mils of the 
filtrate are made acid with acetic acid, an excess of calcium chloride added, 
and allowed to stand in a warm place for three hours. Then filter, wash 
with hot water, transfer precipitate to a flask with as small a quantity 
as possible of water, add 10 mils concentrated sulphuric acid, and titrate 
with N/10 permanganate. 

One mil N/10 permanganate = .0046 gram glycerin. 

The method depends on the oxidation of the glycerin to oxalic acid, 
and the subsequent precipitation of the latter as calcium oxalate. The 
latter should be titrated and not ignited and weighed as CaO, as it may 
be contaminated with sulphate, silicate, and other impurities. 

MANNITOL 

The most important polyhydric alcohol from the point of view of the 
drug chemist is mannitol or mannite. It is a reputed constitutent of 
manna, a concrete saccharine exudation of Fraxinus ornus (Oleacese), 
a species of ash growing in the Mediterranean countries and Asia Minor. 



HYDROCARBONS— ALCOHOLS— ETHERS 



551 



Mannitol has the composition 

CH 2 (OH)CH(OH)CH(OH)CH(OH)CH(OH)CH 2 OH. 

It is a colorless, crystalline substance, with a sweet taste, soluble in water 
and hot alcohol, but insoluble in ether. It exists in several modifications, 
differing principally in their optical properties. It does not reduce 
Fehling's solution. 



Manna 

Manna is credited with possessing laxative, demulcent, expectorant, 
and nutritive properties and will occur in remedies for constipation and 
coughs which are especially recommended for children. It is usually 
administered with other laxative drugs such as senna, rhubarb, magnesium 
sulphate, and Rochelle salts. 

Manna is composed of several carbohydrates, among which have been 
identified levulose, dextrose, mannotriose, and mannotetrose, mannite 
or mannitol, small amounts of resin and ash, and about 10 per cent of 
moisture. Tanret gives the mannitol content at from 40-55 per cent. 

The authorities administering the Food and Drugs Act require a 
manna to contain not less than 75 per cent of material soluble in 90 per 
cent alcohol. This material soluble in 90 per cent alcohol was formerly 
considered to consist chiefly, if not entirely of mannitol, but recent investi- 
gations show that this conclusion is erroneous. Lawall and Forman x have 
reported a comparison of several samples of manna with pure mannitol. 









Sample of 


Sample of 


Sample of 


Sample of 
large flake 








so-called 


large flake 


small flake 




Mannite: 


Suspici- 


high grade 


manna at 


manna at 




pure 


ous 


manna 


least 


least 


manna 




crystals 


sample 


purchased 


twenty- 


twenty- 


over 

thirty 

years old 








in open 


five years 


five years 








market 


old 


old 


*Polarization of whole manna 














before inversion 


0° 


73.5° 


72.8° 


73.8° 


78.0° 


45.8° 


Polarization of same after 














inversion 


0° 


52.9° 


39.5° 


59.2° 


51.5° 


37.2° 


Reducing sugars before inver- 




sion 


None 


17.10% 


13.2% 


17.7% 


10.8% 


11.3% 


Reducing sugars after inver- 














sion 


None 


36.4% 


32.6% 


26.6% 


26.8% 


16.6% 


Per cent soluble in 90 per cent 














alcohol 


Entirely 
soluble 














68.8% 


90.5% 


93.7% 


77.9% 


96.7% 



* All of the polarization figures are sugar scale readings in a200-mm. tube, using 26 grams in 100 cc. 
of solution. 

1 J. Amer. Pharm. Ass., 1917, 22. 



552 



ORGANIC SUBSTANCES 



Polarization of ale. sol. ext 
before inversion 



Polarization of same after in- 
version 



Reducing sugars in ale. sol. 
ext. b.fore inversion 



Reducing sugars in same after 
inversion 



Melting-point 

Charring with strong H 2 S0 4 

Fermentation test with yeast 







Sample of 


Sample of 


Sample of 






so-called 


large flake 


small flake 


Mannite: 


Suspici- 


high grade 


manna at 


manna at 


pure 


ous 


manna 


least 


least 


crystals 


sample 


purchased 


twenty- 


twenty- 






in open 


five years 


five years 






market 


old 


old 


0° 


65.3° 


55.1° 


44.5° 


insuf. 
material 


0° 


51.5° 


35.5° 


32.3° 


insuf. 
material 


None 


15% 


16.4% 


H.6% 


insuf. 
material 


None 


30.3% 


33.2% 


23.1% 


msuf. 
material 


163° C. 


131° C. 


123° C. 


140° C. 


140° C. 


None 


Slight 


Slight 


Slight 


Slight 


Nega- 


Positive 


Positive 


Positive 


Positive 


tive 











Sample of 

large flake 

manna 

over 

thirty 

years old 



57.3° 



45. 6 C 



18.7% 



23.9% 

140° C. 
Very- 
Slight 

Positive 



The Bureau of Chemistry in S. R. A. 16, issued Jan. 26, 1916, under 
article 162 sets down the following tentative standard for manna: Manna 
(the dried saccharine exudation of Fraxinus ornus Linne. Fam. Oleaceae) 
occurring in irregular, more or less elongated, flattened, three-sided pieces; 
externally, yellowish white, friable, somewhat waxy; internally, whitish, 
porous, and crystalline in appearance; odor suggestive of maple sugar; 
taste sweet, slightly bitter, and faintly acrid; it should not consist of soft, 
brownish, viscous masses full of impurities, known as fat manna. Mannite 
(soluble in 90 per cent alcohol) not less than 75 per cent; moisture (loss 
at 100° C.) not more than 10 per cent; ash not more than 3 per cent; 
acid-insoluble ash not more than 1 per cent. 

Recently Furlong and Campbell 2 have reported a manna-like incrus- 
tation on a species of Gymnosporia from Northwestern Rhodesia. This 
product had a slightly sweet taste, and was found to contain 4.9 per 
cent of moisture, 54 per cent of dulcitol, 6.4 per cent of reducing sugar, 
and 6.6 per cent of sucrose. The melting-point of the dulcitol was found 
to be 183° (uncorrected) and 188° C. (corrected.) 

Manna-like substances occur on many other species of vegetation 
and have been reported from time to time usually with the designation 
of the country or locality from which they are derived. 

2 Chem. Soc. Proc., 1913, 29, 128. 



HYDROCARBONS— ALCOHOLS— ETHERS 553 

AROMATIC AND TERPENE ALCOHOLS 

The true aromatic alcohols are those substances with an hydroxyl 
group in the side chain and their general properties bear a close relation- 
ship to those of the aliphatic series. The introduction of an hydroxyl 
into the nucleus produces an entirely different group of substances known 
as phenols. 

The aromatic alcohols may be prepared by heating the correspond- 
ing halogen derivatives with water, weak alkali or silver hydroxide, by 
reducing the corresponding aldehydes or ketones, and in certain instances 
by treating the corresponding aldehydes with potash. 

The straight aromatic alcohols are of little importance in drug chem- 
istry, except as they furnish a means of identifying the aromatic balsams. 
Benzyl and cinnamyl alcohols occur in these substances in the form of 
their benzoic and cinnamic esters. 

Of great importance, however, is the terpene alcohol menthol, and to 
a lesser extent borneol. 

Ortho-oxybenzyl Alcohol, C 6 H 4 (OH)CH 2 OH 

This body, known also as Diathesin, occurs in fine crystals, melting 
86°, soluble in water and alcohol, and used as an analgesic, antipyretic, 
and antirheumatic. It possesses phenolic properties due to the hydroxyl 
attached to the nucleus. 

Cuminic or paraisopropyl benzyl alcohol 
-C 3 H 7 



C 6 H 4 < 

X CH 2 OH 

This is a colorless liquid with a burning taste, boiling 246° C, sp. gr. 
.977 at 15° C, readily soluble in alcohol and ether. It may be prepared 
by treating cuminic aldehyde with alcoholic potash. Cuminic aldehyde 
or cuminol is one of the constituents of the oil of Roman Chamomile. 

Cinnamyl Alcohol, C 6 H 5 CH=CHCH 2 OH 

Cinnamyl alcohol is obtained by the hydrolysis of cinnamyl cinna- 
mate or styrene. It crystallizes in needles, having a hyacinth odor, melt- 
ing 35°, boiling 250°, sparingly soluble in water, but readily in alcohol 
and ether. When slowly oxidized in the presence of platinum black it is 
converted to cinnamic aldehyde and finally to cinnamic acid. 

Salicyl Alcohol, C 6 H 4 (OH) -CH 2 OH 

Salicyl or hydroxybenzyl alcohol is a di-substituted benzene and can 
exist in three different forms. The 1-2 derivative is saligenin, obtained 



554 ORGANIC SUBSTANCES 

by the hydrolysis of salicin. It is crystalline substance, melting 82°, 
subliming 100° readily soluble in alcohol and ether, and less readily in 
water. On oxidation it yields salicylous aldehyde and salicylic acid. It 
gives an intense blue color with ferric chloride. Owing to its phenolic 
nature it forms alkali salts which when heated with alkyl halogen com- 
pounds yield the corresponding ethers. 

The meta compound melts 67° and the para 110°. 

Anisyl Alcohol, C 6 H 4 (OCH 3 )CH 2 OH 

This alcohol is obtained on treating anisic aldehyde with sodium 
amalgam or alcoholic potash. It melts 25° and boils 258°. 

Borneol 

Borneol occurs in the free state and in the form of esters in the oils of 
many different plants. The borneo-camphor from Dryobalanops cam- 
phora consist of d-borneol. The same modification occurs in spike and 
rosemary oils. The Z-form occurs as esters and also in the free state in 
the oils of citronella, Matricaria parthenium, valerian, and kousso. The 
acetate has a characteristic fir odor and is present in many coniferous oils. 

CH3 CH3 

\/ 

C 

CH3. / \ 
>C CH 

h/ / 

CH 2 

CH 2 



C 

/\ 

H OH 

Borneol crystallizes in laminae and plates, melting 203-204° boiling 
212°. Its odor is similar to camphor and also resembles amber. Both 
modifications are alike in their chemical properties. On oxidation with 
chromic acid it yields camphor, and with nitric acid camphoric acid results. 
Phosphorus pentachloride converts it into bornyl chloride, and on boiling 
the latter with anilin, camphene is produced. It is very stable towards 
dehydrating agents such as zinc chloride and sulphuric acid, differing 



HYDROCARBONS— ALCOHOLS— ETHERS 555 

thereby from the isomeric isoborneol. T t forms addition products with 
chloral and bromal, the former melting at 56° and the latter 105-109°. 

Borneol can be separated from camphor by heating with succinic acid 
anhydride. The sodium salt of the ester produced is soluble in water 
and therefore easily separated from camphor. The corresponding deriv- 
atives of phthalic acid may be used. 

Bornyval 

Bornyval is borneol isovalerate, CH 3 CH(CH3)CH2COO-CioHi 7j the 
isovaleric acid ester of borneol. 

Borneol isovalerate is a clear aromatic liquid, having an odor resembling 
oil of rosemary and at the same time a weak odor and taste of valerian. 
It is insoluble in water, but dissolves in all proportions of alcohol and ether. 
The liquid boils at 225° to 260° C. under ordinary pressure. At a pressure 
of 50 mm. it boils at 150° to 170° C, its specific gravity is .945 to .951 ; it 
is lsevorotatory, the angle of rotation lying between -30° and 32° in a 
100-mm. tube at 20° C. 

It is said to be useful in the various neuroses. 

Gynoval 

Gynoval is isoborneol isovalerate, CH3CH(CH3)CH2COO-Ci Hi7, the 
isovaleric acid ester of isoborneol. 

It is a colorless neutral fluid of a peculiar aiomatic odor and mild 
oleaginous taste. It is difficultly soluble in water, but easily dissolved 
in alcohol, ether, acetone, chloroform, benzol, and petroleum-benzine. It 
boils at 132° to 138° C, under 12 mm. pressure, and has specific gravity 
of .952-.957 at 15 °C. 

Gynoval dissolves in concentrated sulphuric acid with formation of 
a red-brown color and liberation of an odor of sulphurous and valeric 
acids. On heating glynoval with an alcoholic solution of potassium hydrox- 
ide for several hours on a water-bath it is completely split up into its 
components, and on diluting this saponification liquid, isoborneol separates 
in solid form, while potassium valerate remains in solution. 

The action of gynoval is that of a mild nervine and antispasmodic, 
resembling that of valerian. 

Brovalol, CH 3 CH(CH 3 )CHBrCOO(C 1 oHi 7 ) 

Brovalol is bornyl brom-valerate, a colorless oily liquid having a slight 
aromatic odor, boiling at 163° under 10-mm. pressure, insoluble in water 
but soluble in alcohol, ether, and chloroform. 

It acts as a nervine. 



556 ORGANIC SUBSTANCES 

Menthol, Ci H 19 OH 

Menthol is a saturated secondary alcohol, and the chief constituent 
of peppermint oils from Mentha arvensis and M. piperita. 

It is used to a large extent in medicinal preparations. It will be 
found in antiseptics, refrigerants, stimulants, and carminatives, and is 
almost always a constituent of the numberless gargles, mouth washes, 
and antiseptic liquids in daily household use. It will be found in tooth 
pastes, in ointments recommended for colds, sore throat, catarrh, head- 
ache, neuralgia, earache, toothache, piles, chapped hands, hay fever, insect 
bites, and in Hniments. 

Tablets and powders intended for antiseptics will be composed of men- 
thol with one or more sodium or potassium salts, borate, bicarbonate, 
chloride, sulphate, phosphate, benzoate, and salicylate with perhaps 
eucalyptol, thymol, and methyl salicylate. Mentholated throat tablets 
contain menthol, cocain, oil of anise, eucalyptol, and benzoic acid. The 
antiseptic liquids of the " listerine " type contain menthol, eucalyptol, 
methyl salicylate, thymol, boric acid and Baptisia tinctoria, Wild Indigo, 
and sometimes formaldehyde and its derivative; those of the " glyco- 
thymoline " type contain borates, bicarbonates, benzoates, glycerin, 
eucalyptol, thymol, menthol, Pinus pumilio, colored with cudbear, and in 
certain instances other ingredients. 

Liniments may contain a great variety of substances and with menthol 
there may occur one or several of the following: camphor, cantharides, 
capsicum, thujone, turpentine, sassasfras, rosemary, thyme or mustard 
oils, aconite, belladonna, opium, potassium iodide, iodin, mercury salts, 
ammonia, in a menstruum of alcohol, chloroform, acetone, alcoholic 
soap, some fixed oil, glycerin or acetic acid. 

Tooth powders may contain menthol, myrrh, cassia, oil, sassafras, 
eucalyptol, thymol, methyl salicylate, calcium carbonate and phosphate, 
magnesium carbonate or oxide, calcium peroxide, or magnesium, orris 
root, with and without soap. Practically the same constituents will be 
found in some combination or other in tooth pastes, to which in addition, 
glycerin and coloring matter are added. 

Ointments containing menthol vary in the character of the other 
materials, depending on the uses to which they are to be put. Ointments 
of menthol, camphor, and boric acid in a petroleum vehicle have a wide 
application; ointments with menthol, mustard oil, and aromatic balsams 
in lard constitute another class, and again we find a heterogeneous collec- 
tion embracing menthol, camphor, phenol, turpentine, quinin, and opium, 
in stearic acid recommended for croup, pneumonia, and similar ailments. 
There are many types of formulas, but it would be impossible to note all 
the combinations which are offered. Some of them are exploited with 



HYDROCARBONS— ALCOHOLS— ETHERS 557 

special stress laid on some one ingredient, and some will consist of the 
ordinary antiseptics and refrigerants with an unusual substance added 
to give it the unique character assigned to it. It is sufficient to conclude 
by saying that menthol will be found in nearly all of them. 

Menthol crystallizes in colorless acicular or prismatic crystals, having 
a characteristic odor and a warm aromatic taste followed by a sensation 
of cold when air is drawn into the mouth. It melts 43° C, boils 212°, 
is only slightly soluble in water, but dissolves readily in all the organic 
solvents. When triturated with an equal weight of thymol, camphor, 
or chloral hydrate there results a liquid mixture. 

Menthol is kevogyrate, as it occurs in nature and the commercial 
article is always of this character. Its rotation is —49.30 in 20 per cent 
alcoholic solution or —57.7° in 10 per cent alcoholic solution. When 
oxidized with chromic acid a lsevo ketone, menthone, CioH 8 0, results. 
With permanganate the oxidation goes further with formation of keto- 
methylic and /3-methyladipinic acids, the latter melting 88-89°. 

On heating menthol with benzoic acid anhydride, menthyl benzoate 
is produced. This ester is difficultly volatile with steam and melts 54-55°. 

Menthol has such unique properties that no special directions are 
needed to identify it. Its odor is usually sufficient to determine its pres- 
ence. However, when it occurs in mixtures containing camphor it may 
easily be overlooked, because if the camphor is in excess (and it usually 
is), the odor of the menthol is completely overlooked. It is difficult to 
separate menthol from camphor. 

U. S. P. Method for Determination of Menthol in Oil of Peppermint. — 
Introduce 10 mils of the oil into a flask provided with a ground-glass tube- 
condenser (acetylization flask), add 10 mils of acetic anhydride and about 
1 gram of powdered anhydrous sodium acetate, and boil the mixture gently 
during one hour. Allow it to cool, wash the acetylized oil with distilled 
water, and afterward with sodium carbonate T. S., diluted with an equal 
volume of distilled water, until the mixture is slightly alkaline to phenol- 
phthalein T. S., and then diy it with the aid of fused calcium chloride, 
and filter. Transfer 5 mils of the dry acetylized oil to a tared 100-mil 
flask, note the exact weight, add 50 mils of half -normal alcoholic potassium 
hydroxide V. S., connect the flask with a reflux condenser, and boil the 
mixture during one hour. After cooling, titrate the residual alkali with 
half-normal sulphuric acid V. S., using phenolphthalein T. S. as indicator, 
and calculate the percentage of menthol present by the following formula: 

Percentage of menthol = 



B -(AX 0.021) 



in which A is the result obtained by subtracting the number of mils of 
half -normal sulphuric acid V. S. required in the above titration from the 



558 ORGANIC SUBSTANCES 

number of mils of half -normal alcoholic potassium hydroxide V. S. origi- 
nally taken, and B is the weight of acetylized oil taken. 

Coryfin 

Coryfin is menthyl ethylglycolate, CH 2 (0-C 2 H 5 ) -COCKCioHiq), the 
ethylgly colic acid ester of menthol. It is a limpid, colorless oil, having 
a very faint menthol odor, boiling under 20 mm. pressure at about 155° C, 
soluble in alcohol, ether, and chloroform; difficultly soluble in water. 

When heated with caustic alkalies it is split up into menthol and 
ethylgly colic acid. 

Coryfin is used as a substitute for menthol. 

Validol 

Validol is menthyl valerianate, CH3CH2CH2COOC10H19, with about 
30 per cent of free menthol. 

It is a clear, colorless liquid, of the consistency of glycerin, having a 
mild pleasant odor, distinct from either that of menthol or valerian, and 
a refreshing cool and very faintly bitter taste, insoluble in water, but 
readily soluble in alcohol, ether, chloroform, and oils. It is decomposed 
by alkalies. On warming with sodium hydroxide solution, the odor of 
menthol manifests itself; if then the alkaline solution is acidulated with 
diluted sulphuric acid, the odor of valerianic acid is developed. 

Forman, or Chlormethyl Menthyl Ester, is described in full under 
formaldehyde. 

Estoral is the name given to so-called boric acid menthol ester, which 
is evidently a weak compound, for it is decomposed into its constituents 
by the action of water. It is used in chronic nasal catarrh. 

DIACID ALCOHOLS 

Terpine, CioHis(OH) 2 , exists in two forms cis-terpine and trans-terpine. 
The former majr be represented by the structure 

CH3 \ /CH2 — CH2\ /H 

>C< >C< 

OH / X CH 2 — CH 2 / x C(CH 3 ) 2 OH 



the latter 



OH v /CH 2 ^CH 2x /H 

CIV X CH 2 — CH 2 / \C(CH 3 ) 2 OH 



The former readily adds H 2 and becomes terpin hydrate, from which 
it may be prepared. 

Cineol or Eucalyptol may be regarded as the oxide corresponding to 
this form. 



HYDROCARBONS— ALCOHOLS— ETHERS 559 

Cis-terpine melts at 104° and boils 258° C. 

Terpin hydrate is the product which is of special interest to the drug 
chemist. It is prepared by acting on turpentine, under proper conditions, 
with alcohol and nitric acid, or by the use of hydrogen peroxide, and is a 
colorless, lustrous crystalline body, CioHi 8 (OH)2+H20, with a slight 
aromatic odor and a somewhat bitter taste, melting 116-117° when rapidly 
heated. It loses its water of crystallization when heated for a prolonged 
period at 100°, and sublimes at the same temperature. 

Terpin hydrate is somewhat soluble in water, chloroform, and ether 
and dissolves with ease in hot water, alcohol, and glacial acetic acid. 

Cineol, doHi 8 

Cineol or Eucalyptol may be prepared from terpin hydrate under suit- 
able conditions, but its interest to us lies in the fact that it is an important 
constituent of the oils of Eucalyptus. 

It is a colorless liquid with a characteristic camphoraceous odor, and 
a pungent cooling taste. It boils 176-177° C, and on exposure to a low 
temperature crystallizes into a mass of needles, melting -1° C. Its 
specific gravity is .930 at 15° or .921-.923 at 25°. It is optically inactive. 
It is soluble in all of the ordinary organic solvents, fixed and volatile oils, 
but does not dissolve in water, nor in solutions of the alkalies. 

Cineol is probably an oxide. It gives none of the characteristic 
reactions of the common classes of organic bodies. It does, however, 
give a number of characteristic reactions, some of which are valuable in 
its identification and estimation. When exposed to a freezing mixture 
and treated with an equal volume of syrupy phosphoric acid, it yields a 
phosphate which may be decomposed by hot water with regeneration 
of cineol. 

With bromin, cineol forms CioHi 8 OBr2, which crystallizes in red 
needles; this bromin compound decomposes with ease vielding water, 
bromin, and cineol. 

With a saturated solution of iodin in potassium iodide, cineol yields 
a mass which contains green lustrous deliquescent crystals. 

Cineol reacts with iodol to form a crystalline compound, melting 112°. 
It may be obtained by shaking the sample with the reagent until it is 
dissolved and then warming. As soon as the crystalline addition produced 
separates, it may be separated and recrystallized out of alcohol or benzol. 

When shaken with a fairly strong solution of resorcinol, cineol soon 
forms a white solid which falls to the bottom of the container. 

Dry hydrochloric acid gas conducted into a mixture of equal volume 
of cineol and petroleum ether gives a crystalline precipitate of an 
unstable hydrochloride. 



560 ORGANIC SUBSTANCES 

When oxidized with a warm solution of potassium permanganate 
cineol gives dibasic cineolic acid, C10H16O5, melting 196-197°. 

The presence of cineol in medicinal products is usually apparent by 
the odor. If it is desired to separate it from a mixture such as a mouth 
wash or inhalant, the sample should be diluted with water and subjected 
to steam distillation, by which treatment the volatile constituents will 
be carried over into the receiver and separated from any salts, glycerin 
fixed oils, and other non-volatile substances. The distillate is cooled 
and shaken out with petroleum ether and the solvent separated, dried 
with calcium chloride, and then filtered and subjected to a stream of 
dry hydrobromic or hydrochloric acid which will threw out the cineol. 
After decanting and washing with petroleum ether, the crystals may be 
treated with water and the cineol freed. 

For the determination of cineol in the oils of Eucalyptus there are 
two types of procedures recommended, one depending on the absorption 
of cineol by phosphoric acid, and the other the combination of cineol and 
resorcinol. Each method has its own advocates. 

The method of the U. S. Pharmacopoeia is of the first type. 

Measure 10 mils of the oil, from a pipette, into a round-bottom glass 
dish of 50-mils capacity, which is imbedded in finely broken ice. Add 
10 mils of arsenic acid T. S. and stir until precipitation is complete. When 
the mixture ceases to congeal further, allow it to stand for ten minutes 
in the ice bath. (If at this point a hard mass is formed, add 5 mils of 
purified petroleum benzin, and mix the mass well before proceeding with 
the assay.) Then transfer it immediately to a hardened filter paper, 
about 18.5 cm. in diameter, by means of a pliable horn spatula; spread 
it evenly over the surface of the paper and lay a second hardened filter 
paper over the top. Wrap several thicknesses of absorbent or filter paper 
around the hardened filters, and place the whole between the plates of a 
press and bring to bear all the pressure possible for about one minute. 
Change the outside absorbent papers and press again,. repeating the oper- 
ation, if necessary, until the eucalyptol arsenate is apparently dry, and 
separates readily when touched with a spatula. The pressing is not 
complete when a hard mass remains which is broken up with difficulty; 
and usually two changes of filter paper are required, pressing each time 
for about two minutes; if left too long in the press the compound may 
decompose. Now, transfer the compound completely by means of the 
horn spatula to a glass funnel inserted into a 100-mil cassia flask with a 
neck graduated to 10 mils into tenths. Wash the last portions of the 
precipitate into the flask with a stream of hot distilled water from a wash 
bottle, assisting the disintegration with a glass rod, place the flask in 
boiling water and rotate it until the compound is thoroughly broken up. 
Then add enough distilled water to cause the eucalyptol to rise into the 



HYDROCARBONS— ALCOHOLS— ETHERS 561 

neck of the flask, cool it to room temperature and read its volume. This 
volume, multiplied by 10, shows the percentage of eucalyptol (cineol) in 
the oil. 

The following method, which depends upon the solubility of the 
resorcin -eucalyptol in excess of solution of resorcin, is stated to give results 
more accurate than the phosphoric acid method usually employed. Ten 
mils of the essence is introduced into a 100-mil Hirschsohn flask and well 
shaken up with about 80 mils of 50 per cent solution of resorcin for five 
minutes, the non-soluble portion of the oil is allowed to separate, then 
more resorcin solution is added to bring the non-cineol portion into the 
graduated portion of the neck, when its volume is read off. Oils which 
are very rich in cineol should first be diluted with an equal volume of 
essential oil of turpentine, or the cineol-resorcin compound will crystallize 
out, and in so doing retain some of the non-cineolic constituents. Obvi- 
ously in this case the volume of the liquid read off must be multiplied by 
2 to give the percentage. Not only is the method more accurate and 
convenient, but by mere distillation or evaporation, the resorcin cineol 
compound is decomposed; the residual resorcin, evaporated to dryness, 
may be used again for another cineol determination. 

Eucalyptol enters into the composition of a number of popular remedies, 
including mouth washes and gargles and catarrh and hay fever remedies 
of the hyomei type. Its presence in most of these mixtures is apparent 
by the odor. It is also a component of tablets of the same general compo- 
sition as the gargles and douches, and is dispensed with sandal-wood oil 
and creosote in capsules. 

ETHERS 

Ethers are related to the metallic oxides in the same way as the alcohols 
are related to the metallic hydroxides. CH3OH corresponds to KOH and 
CH3OCH3 corresponds to KOK. The term " ether " is also applied to 
the esters of acetic and other acids, but these are, strictly speaking, ethereal 
salts, and will be considered in their proper place in a subsequent chapter. 

With the exception of methyl ether, which is a gas, they are mobile, 
volatile inflammable liquids, lighter than water and boiling at a lower 
temperature than the corresponding alcohols. They are even more inert 
than alcohols, as they are not acted upon by alkalies of alkali metals or 
by phosphorus pentachloride in the cold. They do not combine with 
dilute acids, but when heated they yield ethereal salts with the elimina- 
tion of water, and form substitution products with chlorine and bromin. 



562 ORGANIC SUBSTANCES 



Ethyl or Sulphuric Ether, C2H5OC2H5 



Ethyl ether is the only substance of this class which is of importance 
in our work, and as it is used almost entirely as an individual, and but 
seldom in mixtures, the question of its determination is not of great 
moment. For its identification its inertness and failure to give character- 
istic reactions for alcohols, aldehydes, and ketones in conjunction with 
its physical tests are sufficient. 

The analyst will often be called upon to determine the availability 
of a sample for anesthetic purposes, and in pharmaceutical establish- 
ments to pass upon its quality for manufacturing; and in special cases 
for a reagent in high-grade analytical work. 

The established grades of ether include: 

Anhydrous ether, which is practically pure ethyl oxide. 

Anesthetic ether, which complies with the requirements of the Pharma- 
copoeia which may contain alcohol up to 4 per cent and traces of acetal- 
dehyde, acids, and water. 

Commercial ether, which contains at least 95 per cent by weight of 
ethyl oxide. 

For some purposes one will encounter: 

Ether U. S. P. 1880, called " 80 ether," composed of about 74 per cent 
of ethyl oxide and 26 per cent alcohol containing a little water, specific 
gravity .750 at 15° C. 

Stronger ether U. S. P. 1880 containing 94 per cent ethyl oxide and 
about 6 per cent of alcohol containing a little water, specific gravity .716 
at 25° C. 

Ether composes about one-third of Spirit of Ether and of Compound 
Spirit of Ether or Hoffmann's Anodyne. It is also present in some 
ethereal tinctures, lobelia, ferric chloride, valerian, belladonna, etc. 

Dr. Chas. Baskerville and Dr. W. A. Hamor l have made an exhaust- 
ive study of ether and devised a scheme for the examination of the product 
for analytical and anesthetic purposes with particular reference to the 
detection of avoidable impurities. The standards adopted by these 
gentlemen and the procedures to be employed for determining the necessary 
data are quoted herewith. 

1. Specific Gravity. — Determine the specific gravity by means of a 
pyknometer at 15° C. 

2. Boiling-point. — In the case of anesthetic ether, at least 97 per cent 
of the sample should distill over between 34° and 36° C. (at 760 mm.), 
and none of it should come over above 37°; after the fractionation to 
this temperature, no residue should remain in the fractionating vessel. 

1 J. Ind. and Eng. Chem., 1911, 3, 301 and 378. 






HYDROCARBONS— ALCOHOLS— ETHERS 563 

In the case of the anhydrous ether, at least 99.50 per cent should dis- 
till off between 34° and 36°, and none should come over above 36°. 

3. Organic Impurities. — When 20 mils of the sample are added drop 
by drop to 20 mils of pure concentrated sulphuric acid, which is kept 
cooled during the tests and which is contained in a glass-stoppered bottle 
previously rinsed with concentrated sulphuric acid, the resulting solution 
should be colorless. The sulphuric acid should be gently shaken after the 
addition of each drop of ether in order to ensure perfect solution. 

4. Odor. — When 50 mils of the sample are allowed to evaporate spon- 
taneously on filter paper, 10 cm. in diameter, contained in a flat porcelain 
dish, the paper should be odorless after the evaporation of the ether. The 
latter should be added to the paper in portions in such a manner as 
completely to moisten it. In the case of a decided odor being imparted to 
the filter paper, the ether should be rejected, but for further information 
may be tested for such impurities as " heavy oil of wine," fusel oil, etc. 

5. Residue {Extractive Matter, Odor and Acidity). — (1) When 25 mils of 
the sample are allowed to evaporate spontaneously in a clean, dry glass 
dish, the moist residue must possess no odor, and must neither redden 
nor bleach blue litmus paper; this residue must evaporate completely 
on a water-bath — that is, there should be no fixed residue. 

(2) 100 mils of the ether under examination are allowed to spontane- 
ously evaporate in a flask until about 15 mils remain in the vessel. This 
residue should be free from color and foreign odor, and should comply in 
full with the following tests: (a) When 5 mils are allowed to evaporate 
at room temperature after the addition of 2 mils of water, the residue 
should neither redden nor bleach sensitive light-blue litmus paper. (6) 
When another portion of 5 mils is allowed to evaporate on a 9-cm. filter 
paper contained in a porcelain dish, there should be perceptible no foreign 
odor (amyl compounds, empyreumata, pungent matters, etc.) as the last 
portions disappear from the paper, and the latter should be left odorless, 
(c) On the addition of the remaining 5 mils to 5 mils concentrated sul- 
phuric acid, kept cool during the test and contained in a glass-stoppered 
tube previously rinsed with concentrated sulphuric acid, there should 
result no perceptible coloration. Anesthetic ether should comply in full 
with these tests. 

6. Acidity. — (1) When 25 mils of the sample are allowed to evaporate 
at room temperature after the addition of 5 mils of pure water the residue 
should neither redden not bleach sensitive light blue litmus paper. 

(2) When 20 mils of pure ether are shaken with 10 mils of pure water 
and 2 drops of phenolphthalein, the same depth of color should result 
on adding an equal amount of N/100 potassium hydroxide solution as 
in a test using pure water alone. In the case of ether intended for special 
analytical purposes, the addition of .3-5 mil of N/100 potassium hydroxide 



504 ORGANIC SUBSTANCES 

should produce an alkaline reaction. When more than 1 mil is required, 
the ether should be rejected for anesthetic purposes. 

7. Water and Alcohol {Exclusion Tests for Pure and Anhydrous Ethers). 
(1) (This test is superfluous if the ether possesses a correct specific grav- 
ity.) A minute quantity of powdered fuchsin (rosaniline acetate), pre- 
viously dried at 100° C, is placed in a dry test-tube, 10 mils of the ether 
are added, and the tube is corked and shaken well. In the case of pure 
and anhydrous ethers, no amethystine color — even faint — should result. 
If the coloration imparted to the ether is considerable, the approximate 
percentage of impurity is determined by Allen's method. 1 

(2) When several milligrams of anthraquinone and the same amount 
of sodium amalgam are added to 10 mils of the ether there should result 
no formation of red or green substances. The presence of both water 
and alcohol may be detected by this test. 

8. Water {Exclusion Tests for Pure and Anhydrous Ethers). — (1) On 
shaking 1 gram of anhydrous copper sulphate with 20 mils of ether, the 
salt should not assume a green or blue color. 

(2) In important or doubtful cases, the test with amalgamated alum- 
inum may be used. If the ether contains no moisture and it responds 
to the tests under " Water and Alcohol " the presence of the latter may 
be really assumed, especially if the colors are marked. 

9. Water and Aldehyde {Exclusion Test for Pure and Anhydrous 
Ethers). — When 15 mils of the sample are placed in a perfectly dry test- 
tube and a piece of metallic sodium about 5 mm. in diameter is added, 
there should result only a slight evolution of gas and the sodium should 
not possess, after standing six hours, a white or yellow coating and the 
ether should not be colored or turbid. Only when the ether has been 
previously treated with sodium will the latter retain a distinct metallic 
luster at the expiration of the test; otherwise the metal becomes coated 
with sodium hydroxide. In the presence of aldehyde the sodium hydrox- 
ide is more or less colored. 

10. Acetaldehyde. — (1) Apply the fuchsin-sulphurous acid test of 
Francois. Pure ether should not restore the color to fuchsin decolorized 
by sulphurous acid. The red-violet color should be faint in the case of 
anhydrous ether. 

(2) On covering 5 grams of solid potassium hydroxide, in freshly 
broken pieces about 5 cm. in diameter, with 30 mils of the sample, and 
allowing the mixture to stand for six hours, tightly closed and protected 
from the light, and occasionally shaking, the potassium hydroxide should 

1 All colorimetric tests should be performed preferably with a colorimeter, having 
tubes with an internal diameter of 1.5 cm. But other forms of vessels may be used; 
for example, a ground-glass-stoppered Erlenmeyer flask, of suitable size for the amounts 
of liquid prescribed in the test, has been found to answer. 






HYDROCARBONS— ALCQHOLS— ETHERS 565 

not acquire a yellowish color, no yellowish or brown colored substance 
should separate, and the ether should not become turbid or assume any 
color. This is recommended as the exclusion test for anesthetic ether. 
Pure or anhydrous ether should give no response after standing twenty- 
four hours. 

(3) In the absence of alcohol, as indicated by these tests for water and 
alcohol, and confirmed by those given below, the following test may be 
applied for the detection of aldehyde: When 10 mils of the sample are 
agitated with 2 mils of Nessler's solution, a yellow color or black pre- 
cipitate is indicative of the presence of aldehyde. Pure ether is indif- 
ferent toward this reagent, but it is impossible to purchase ether which 
does not show a yellow color within fifteen minutes. For anhydrous or 
anesthetic ether, it is sufficient to require, therefore, that no black pre- 
cipitate settles out, although the mixture may assume an opalescent 
yellow color. 

11. Alcohol. — The occurrence of alcohol may be ascertained as 
follows : 

(1) In the presence of water, a portion of the sample is dried over 
anhydrous potassium carbonate and then tested, in 10-mil portions, 
with (a) rosaniline acetate, and (6) anthraquinone sodium amalgam. 

(2) In the absence of other than mere traces of acetaldehyde, by 
Lieben's iodoform test. 

(3) In the presence of acetaldehyde, by this method: The amount 
of aldehyde in 25 mils is approximately determined colorimetrically by 
Francois method. A portion of 25 mils is then agitated with 25 mils 
pure water in a ground-glass-stoppered bottle, and the aqueous layer, 
which will show an increase in volume greater than 10 per cent of the 
ether taken depending on the amount of alcohol present, is removed and 
freed from dissolved ether by careful warming at 40° C, until ether is 
expelled. The alcohol in the water is then oxidized by potassium dichro- 
mate and sulphuric acid, the aldehyde produced is distilled off, and the 
amount contained in the distillate is determined approximately colori- 
metrically. By comparison with the percentage of aldehyde found as 
originally existing in the ether, the amount of alcohol may be calculated; 
however, the authors do not recommend the method as an exact quanti- 
tative one, but only as one for arriving at the approximate amount of 
alcohol contained in ether, and as a confirmatory test. 

12. Peroxides (Exclusion Test for Ether of all Grades). — When 2 mils 
of a 10 per cent cadmium potassium iodide solution are well shaken with 
10 mils of the sample, there should result no liberation of iodin within 
one hour. This may be easily determined by adding starch solution, 
although the yellow color which results in the presence of the merest 
traces of peroxides is easy to distinguish. The presence of peroxides 



566 



ORGAMIC SUBSTANCES 



may then be confirmed by any of the other tests devised by the authors, 
or by Jorissen's vanadic acid test. 

Ether prepared from alcohol denatured with methyl alcohol and 
pyridin bases often contains methyl ethyl ether and acetone. Frerichs l 
describes tests for detecting these bodies. For the detection of the first 
named a 250- or 500-mil sample, the boiling-point of which has been ascer- 
tained, is distilled and the boiling-point of the first 50 mils noted. If 
essentially lower than that of the sample the presence of the impurity is 
indicated, assuming of course that the absence of other usual impurities 
has been assured. As ordinarily determined the temperature of the boiling- 
point rises until it shows the boiling-point of pure ether. Frerichs shows 
an apparatus which can be operated so that the boiling-point may be 
observed for a long time. One hundred mils of the sample together with 
a glass capillary sealed at the top to avoid bumping are introduced and 



m 




100 mils 



heat applied by insertion of base into an air-bath, the thermometer resting 
in neck (A) so that bulb reaches to X. Neck B is connected with a reflux. 
As soon as a steady and vigorous return from B is noted the thermometer 
will indicate a constant boiling-point. 

To detect acetone 100 mils of ether are shaken vigorously with 10 mils 
water. The ether is withdrawn and the aqueous liquid divided into 
two parts. To one 10 drops sodium nitroprusside solution are added, 
6 drops sodium hydroxide, 5 mils water and then acetic acid in slight 
excess; if the liquid does not completely decolorize and a reddish or 
violet color appears acetone is indicated. The second portion is then 
tested with iodine and ammonia and heated until any black precipitate 
disappears and the liquid becomes clear and bright yellow. A crystalline 
precipitate of iodoform indicates acetone. 

Ether is one of the substances which has to be declared upon the label 
if it occurs in mixtures intended to be used as drugs. It is classed as a 
derivative of alcohol. The determination of ether in alcoholic mixtures 

1 Apoth. Zeit., 28, 628. 



HYDROCARBONS— ALCOHOLS— ETHERS 567 

has been described under Alcohol, page 539. With preparations which 
are more complex than the ordinary alcohol ether mixture, the alcohol 
and ether should be separated from the other substances by distillation, 
first diluting the sample with water. The distillation is best accomplished 
by heating 50-100 mils of the sample in a round-bottom flask, using a 
direct flame and running the distillate through a long and well-cooled 
condenser into a receiver surrounded with ice, the neck of which is well 
over the adapter, and stuffed with absorbent cotton. The distillate can 
then be transferred to the apparatus used for determining the ether. After 
the latter has been estimated the alcohol can be estimated in the aqueous 
portion by distillation. 

Determination of Small Amounts of Alcohol and Water in Ether. 
Mallinckrodt and Alt. 1 — The flask used was a 100-mil Regnault pykno- 
meter for taking the density of solids. It is best to have two and make 
the analysis in duplicate. 

Fifteen grams of potassium carbonate dried at 200 to 250° are placed 
in the bulb A and accurately weighed after replacing the stem B. Remove 
the stem and introduce quickly 50 mils of the ether for analysis. Replace 
stem and allow the flask to stand fourteen hours with frequent shaking. 
By removing the stopper and holding the inverted flask in the warm hand, 
the ether can be filtered out through the cotton plug X. Care must be 
used to insure a clear filtrate, otherwise there will be a loss of potassium 
carbonate. Examine the filtrate after standing to see that no finely 
divided carbonate has separated out. Fill the upper enlargement B with 
absolute ether and cause it to be drawn in by pouring some of the ether 
over the bulb. Shake well and expel the ether as before. Wash four 
times in this manner, which removes the alcohol from the salt. Now 
dry the flask, with cap C removed, at 50° until the carbonate can be shaken 
down into the flask. Remove the stem and replace it with a drying 
tube filled with carbonate of potassium to prevent access of external 
moisture and d y for 1 hour at 50°. Remove the drying tube and after 
sweeping out the remaining ether vapor with gentle suction for fifteen 
seconds, replace the stem and cool in a desiccator and weigh. Since 
it does not require much ether vapor to affect the weight, care is required 
to secure its complete removal without introducing moisture from an 
excess of air. A second weighing should be made after drying again for 
half an hour. The weights should be constant within about 4 mg. The 
difference between the weights of the potassium carbonate before and 
after treatment with ether is the weight of water in the sample taken. 
For the alcohol analysis, treat 100 grams of the sample with 40 grams 
of freshly dried potassium carbonate for fourteen hours in a glass-stopped 
flask, shaking frequently. The pyknometer is filled with the clear ether 
1 J. Ind. and Eng. Chem., 1916, 8, 811. 



568 



ORGANIC SUBSTANCES 



and the specific gravity is determined at exactly 25° on the hydrogen 
scale. The per cent of alcohol may then be read off from the curve. 
Obviously if this curve is to be used, the gravity must be made in a bath 
at exactly 25° on the international hydrogen scale or else a new curve 
made by the operator at the temperature of his thermostat, which is a 
simple matter. 





































1 


































.7150 
























































































FIG. 1. 














































.7140 






SPECIFIC GRAVi: 


riES OF 


ETHER-ALCOHOL 


































^MIXTURES AT 25° C. HYDROGEN SCALE 






























•£.7130 
O.7120 


































































































































































































































































































O.7110 
w .7100 


































































































































































































































































































.7090 




























































































1 








































































1 



















































2 3 

Alcohol per cent by weight 




ORGANIC PEROXIDES 

These substances are related to the metallic peroxides in the same way 
that ethers are related to the oxides, and alcohols to the hydroxides. They 
may be considered as hydrogen peroxide in which the hydrogen atoms 
have been replaced by organic radicles. 

R— O 
R— 6 

There are only two of these substances at present which have attained 
any commercial importance and which may be encountered in analytical 
practice, benzoylacetyl peroxide or acetozone and disuccinyl peroxide or 
alphozone. 



HYDROCARBONS— ALCOHOLS— ETHERS 569 

These organic peroxides are used as intestinal antiseptics in typhoid 
and enteric fevers, and also for local infections where they can be brought 
in contact with the diseased surface such as ulcers, abscesses, inflammation 
of the mucous membranes, and infectious skin diseases. Acetozone is 
recommended as an antiseptic in ophthalmic, aural, and nasal practice, 
and is dispensed in an oil medium with chloretone. 

Benzoylacetyl peroxide, C 6 H 5 CO • O • O • OCCH 3 

Acetyl-benzoyl peroxide occurs in white, shining crystals, melting at 
36.6° C. When heated it slowly decomposes and volatilizes. Water at 
25° C. dissolves one part in 1.560 or .639 gram in 1000 mils. It is soluble 
in oils to the extent of about 3 per cent, slightly soluble in alcohol, and 
fairly so in ether, chloroform, and carbon tetra-chloride, though all sol- 
vents slowly decompose it with the exception of neutral petroleum oils. 

In the presence of water it undergoes hydrolysis and slowly decomposes. 

As found in the market, acetozone is of a grayish-white color, possessing 
the properties of the crystalline substance, with the exception that the 
absorbent powder employed is insoluble. 

When dispensed at the bedside the powder is mixed with water and 
the solution consumed by the patient; but when sold by the druggist 
on prescription it is often put up in capsules. 

Succinic dioxide or Disuccinyl peroxide, (COOHCH2CH 2 CO) 2 02 

It is a fluffy, white, crystalline powder, the crystals being small irregu- 
lar plates. It dissolves in 30 parts of water at ordinary temperature. It 
is moderately soluble in alcohol, acetone, and ethyl acetate, sparingly solu- 
ble in ether, insoluble in benzene, chloroform and petroleum ether. Odor- 
less or nearly so; softens at 115° C. and melts at 127° C. with decompo- 
sition. When brought into a flame it explodes, but it does not explode 
on percussion or friction. It deteriorates slightly on continued exposure 
to air, but if kept tightly stoppered and in a dark place it remains 
unchanged indefinitely. 

It is a powerful oxidizing agent, liberating iodin from potassium iodide. 
It can be identified by its physical properties and its powerful oxidizing 
action. To test its strength add 2 grams of potassium iodide to 1 gram 
of alphozone dissolved in 60 mils of distilled water. To this slowly add 
decinormal solution of sodium thiosulphate with constant agitation until 
the red-brown color of the iodin is just discharged. Each mil of sodium 
thiosulphate solution is equivalent to .0117 gram of alphozone; 1 gram 
of pure alphozone is equivalent to 85.41 mils decinormal sodium thio- 
sulphate solution. 



CHAPTER XVI 

ALDEHYDES AND KETONES 

ALDEHYDES 

This class of organic bodies includes the two very important medicinal 
agents, formaldehyde and chloral. The aldehydes are derived from the 
primary alcohols by the removal of two atoms of hydrogen from the 
— CH2OH group, thus methyl alcohol on mild oxidation gives formal- 
dehyde. They are named after the fatty acids which they yield on oxi- 
dation. 

With the exception of the gaseous body formaldehyde, whose physical 
properties are unknown, the lower members of the aldehyde series are 
colorless, mobile, neutral, volatile liquids, soluble in water, though the 
solublity decreases as the number of carbon atoms increases. The higher 
aldehydes are usually waxy solids, insoluble or nearly so in water but 
readily soluble in alcohol and ether. They are closely related to the 
ketones because they are similar in constitution, both classes containing 
the carbonyl group = CO. The lower members form crystalline addition 
compounds with sodium bisulphite, which are soluble in water, but insol- 
uble in alcohol and ether, and are decomposed on warming with acids or 
alkalies with regeneration of the aldehyde. They form oximes with hydro- 
hydroxylamine, and hydrazones or phenylhydrazones with phenylhydra- 
zine, a molecule of water being split off in the reaction. Both oximes 
and hydrazones are usually decomposed by hot concentrated hydro- 
chloric acid with regeneration of the aldehyde. 

Aldehydes on reduction with nascent hydrogen yield primary alcohols. 
With phosphorus pentachloride they give dihalogen derivatives of the 
paraffins, the oxygen of the =CO group being displaced by two 
atoms of chloride. Acet aldehyde gives dichlorethane, called ethylidene 
chloride, because it contains the ethylidene group, CH 3 • CH • CH3CHO 
+PCl 5 = CH3CHCl2+POCl 3 . Aldehydes combine directly with hydro- 
cyanic acid to form hydroxycyanides, 

\ /° H 
CO+HCN- >C< 

x X CN 

570 



ALDEHYDES AND KETONES 571 

Aldehydes possess a number of characteristic properties which differ 
essentially from the ketones. On exposure to the air they are quite 
easily converted to fatty acids, they are readily oxidized by an ammoniacal 
solution of silver oxide, forming a silver mirror, and reduce Fehling's 
solution. They form addition products with ammonia 



> 



\ / 0H 
CO+NH3= >C< 

/ X NH 2 



which are usually crystalline, soluble in water, and yield the aldehyde 
again on treatment with dilute acids. They combine with two molecules 
of- alcohols to produce acetals, 

HOC2H5 \ /OC2H5 
C=0+ = >C< +H 2 0. 

HOC2H5 / X OC 2 H 5 

They are unstable in presence of alkalies, by which thay are converted 
to brown resins. Aldehydes undergo .polymerization which may take 
place spontaneously, but usually on the addition of some substance such 
as zinc chloride or sulphur dioxide. The common form of polymerization 
is the combination of three molecules of the aldehyde to form paralde- 
hydes such as paraformaldehyde or trioxymethylene and paracetalde- 
hyde often called simply paraldehyde. The constitution of these polymers 
are usually represented as follows : 







H2C CH2 

I I 

o 

\ / 



c 

H 2 

Paraformaldehyde 

They are decomposed into the original aldehydes on distillation with 
dilute mineral acids. They do not show the characteristic reactions of 

aldehydes and do not contain a ^>CO group. 

Formaldehyde is an excellent deodorant and disinfectant, but is too 
irritating for general medicinal use. As a disinfectant it has quite taken 



572 ORGANIC SUBSTANCES 

the place of sulphur and it is almost universally used in embalming fluids. 
It is also valuable as an insecticide and a sweetened solution of commer- 
cial formaldehyde is a valuable agent for destroying the common housefly. 

In small amounts formaldehyde will sometimes be found in tooth 
pastes, washes, gargles, whooping cough inhalants, and eye lotions, and 
in fluid preparations recommended as deodorants. Paraformaldehyde or 
trioxymethylene is sold in tablet form as a remedy for hoarseness and sore 
throat and also for diarrhea, as it is somewhat astringent. It is dispensed 
in collodion in wart remedies and the vapors of the pure substance are 
recommended for consumptives and as an ingredient of surgical bandages 
and dressings. During the last decade a number of true and pseudo 
derivatives and compounds of formaldehyde have appeared on the market 
and will be discussed subsequently. 

Hexamethyleneamine is probably the most important derivative of 
formaldehyde medicinally, and is used as an antiseptic for the genito- 
urinary tract in all infectious diseases common to that locality, also as a 
urinary disinfectant in typhoid and for aborting coryza and acute con- 
ditions of the nasal passages. 



Formaldehyde, HCHO 

Formaldehyde or methaldehyde is known only in dilute solution and 
in the form of a gas at high temperatures. It would probably be a gas 
at ordinary temperature. The aqueous solution of formadehyde has a 
very penetrating, suffocating odor and a neutral reaction. It is a powerful 
reducing agent and readily undergoes oxidation, producing formic acid; 
and when treated with reducing agents it is converted to methyl alcohol. 
It reduces ammoniacal silver oxide, combines directly with sodium bisul- 
phite, and forms formaldoxime with hydroxylamine, which readily under- 
goes polymerization. 

When an aqueous solution of formaldehyde is evaporated paraformal- 
dehyde resu ts. The latter is a colorless amorphous substance, subliming 
readily and melting 171°. When strongly heated it is completely decom- 
posed into pure gaseous formaldehyde, but as the gas cools paraformal- 
dehyde again results. When heated with a large amount of water it is 
reconverted into formaldehyde. 

Formaldehyde forms several polymeric modifications. When its aque- 
ous solution is treated with lime water or other weak alkali formose 
results which is a mixture of substances belonging to the sugar group. 

The aqueous solution of formaldehyde containing not less than 37 
per cent of the gas is recognized in the Pharmacopoeia. 



ALDEHYDES AND KETONES 573 

Compositions for generating formaldehyde vapors consist of the solid 
substance or a solution mixed with permanganates or alkali peroxides 
or bisulphites. The general idea is that formaldehyde is held by the 
alkali or bisulphite and on the addition of permanganate in aqueous solu- 
tion the gas is liberated. In solid products the permanganate or per- 
oxide is included and simple addition of water liberates the formaldehyde. 
The oxidation of formaldehyde in soap solutions is prevented by the 
addition of sulphite. 

The identity tests given by formaldehyde are very striking, and are 
performed with an aqueous solution of the substance. The bright rose 
color given with sulphuric acid and resorcin has been described in detail 
under Methyl Alcohol page, 531. The morphin test may be carried out 
by adding a few drops of the suspected liquid to 5 mils sulphuric acid, 
cooling and pouring a little of the liquid on some morphin crystals on a 
white porcelain surface, when a deep purple color will be produced. 

Mullikin's beta-naphthol test is carried out by mixing a small quantity 
of the solution under examination with dilute alcohol 1-2 and adding 
about .005 gram beta-naphthol, 3 to 5 drops of hydrochloric acid and boil- 
ing. The precipitate is collected on a filter, washed with alcohol 1-2, 
and recrystallized out of boiling alcohol. The methylenedibetanaphthol 
formed melts 189°. 

A modification of the morphin test suggested by Bonnel directs that 
the surface of a dish or watch-glass should be moistened with sulphuric 
acid containing a trace of morphin and exposed to the vapors rising from 
the sample under investigation. If formaldehyde is present in the vapors 
the characteristic purple shade will be developed. 

The analyst will often be called upon to determine the strength of 
formaldehyde solutions for sale on the market. 

The hydrogen peroxide method is official in the Pharmacopoeia. 

Transfer 3 mils of Solution of Formaldehyde to a tared flask contain- 
ing 10 mils of distilled water, tightly stopper and weigh accurately. Add 
to the contents of the flask 50 mils of normal potassium hydroxide V. S., 
and follow this immediately but slowly through a small funnel with 50 
mils of solution of hydrogen dioxide which has previously been rendered 
neutral to litmus with potassium hydroxide. Now heat the mixture 
cautiously on a water-bath for five minutes, shaking occasionally during 
this time; allow the mixture to cool, rinse the funnel and sides of the flask 
with distilled water and, after allowing it to stand thirty minutes, titrate 
with normal sulphuric acid V. S., using litmus T S. as indicator. It 
shows not less than 37 per cent of CH2O, correction being made for free 
acid if present. 

Each mil of normal potassium hydroxide V. S. corresponds to .03002 



574 ORGANIC SUBSTANCES 

gram of CH2O. Each gram of solution of Formaldehyde corresponds to 
not less than 12.3 mils of normal potassium hydroxide V. S. 

The writer has found that very good results can be obtained by the 
iodine method. For this purpose an approximate N/5 Iodin is used, the 
exact titer of which need not be known because it is advisable to run a 
blank at the same time. The thiosulphate should of course be accurately 
standardized. Twenty mils of the solution accurately measured are 
introduced into a 500-mil graduated flask and made up to the mark with 
distilled water. Five mils of this solution, measured with a pipette, are 
placed in a glass-stoppered bottle, 30 mils N/1 sodium hydroxide added, 
and then with constant agitation the iodin solution is added from a burette, 
noting the amount, until the mixture appears bright yellow. After shak- 
ing for a minute 40 mils of N/1 sulphuric acid is added and the excess of 
iodin determined by titrating with N/10 thiosulphate. A blank is then 
run using the same quantities of alkali, iodin, and acid, the difference 
showing the amount of iodin consumed by the formaldehyde. One mil 
N/10 iodin is equivalent to .0015 gram formaldehyde. In calculating 
the percentage by weight the result must be divided by the specific 
gravity of the formaldehyde solution used. 

Formaldehyde can be determined in soap solutions by precipitating 
the fatty acids with sulphuric acid, filtering, and determining the formal- 
dehyde in the filtrate by the iodin method, the iodin being added before 
the alkali is introduced. After rendering alkaline the requisite N/1 sul- 
phuric acid is added and the excess of iodine determined by thiosulphate. 

Colorimetric Method. Collins and Hanzlik. 1 — Aliquot portions of the 
formaldehyde solution are measured into Nessler tubes, 2 mils of phloro- 
glucinol reagent (.1 gram of phloroglucinol dissolved in 10 mils of 10 per 
cent sodium hydroxide solution) is added to each, and the mixtures are 
diluted to 50 mils. After three minutes, the colorations obtained are com- 
pared with standard colors. The latter are prepared from definite quan- 
tities of Congo red solution (0.025 per cent in water containing 5 per cent of 
alcohol) and methyl orange solution (.01 per cent in water) ; 2.5 mils of the 
Congo red solution diluted to 50 mils gives the same coloration as 50 mils 
of .001 per cent formaldehyde solution when both are viewed in a column 
12 cm. in depth. Different samples of Congo red do not always give the 
same depth of color, and the solution should be standardized against potas- 
sium bichromate; 2.5 mils of the .025 per cent Congo red solution diluted to 
50 mils should have the same tint as a mixture of 1.7616 grams of potassium 
bichromate and 11.5537 grams of sulphuric acid diluted to 50 mils. The 
addition of methyl orange solution to the standards is necessary only 
when dealing with low concentrations of formaldehyde. The propor- 
tions of Congo red and methyl orange corresponding with different con- 
1 J. Biol. Chem. 1916, 25, 231. 



ALDEHYDES AND KETONES 



575 



centrations of formaldehyde are given in the following table, the mix- 
tures being diluted to 50 mils and viewed in a 12-cm. column: 





Congo red 


Methyl Orange 




Congo red 


Methyl Orange 


Formaldehyde 


(0.025 per cent 


(0.01 per cent 


Formaldehyde 


(0.025 per cent 


(0.01 per cent 




solution) 


solution) 




solution) 


solution) 


Per Cent 


Mils 


Mil 


Per Cent 


Mils 


Mil 


0.005 


20.0 





0.001 


2.5 





0.0033 


11.0 





0.0005 


0.85 


0.4 


0.0025 


9.0 





0.0040 


0.65 


0.35 


0.002 


8.0 





0.0002 


0.23 


0.18 


0.0016 


5.0 





0.00014 


0.20 


0.15 


0.00125 


4.0 





0.0001 


0.13 


0.10 



To determine formaldehyde in urine, the phosphates present must be 
removed by treatment with sodium hydroxide solution and filtration before 
the above method is applied. Experiments with known quantities of 
formaldehyde showed that the method was more accurate than several 
other methods with which it was compared. The chlorimetric method 
may be used to determine hexamethylenetetramine in urine, etc., the 
latter is distilled without the addition of acid and the process applied to 
the distillate. If formaldehyde is also present in the urine, this must be 
determined previously and its quantity deducted from the total amount. 



Paraformaldehyde and Trioxymethylene 

The valuable properties of formaldehyde and the inconvenience of 
handling an aqueous solution soon created a demand for a solid form of 
the substance, and it is now marketed to a large extent in the polymerized 
condition. 

There is a confusion in some minds regarding the terms paraformal- 
dehyde and trioxymethylene, they are often used synonymously and with 
good reason, since their formation is so nearly identical, and for the infor- 
mation of the workers in this field who may be involved in legal quibbles 
concerning these points reference will be made here to the work of Auer- 
back and H. Barscall, 1 whose work on the polymers of formaldehyde may 
be summarized as follows : 

Paraformaldehyde is an amorphous colloidal substance with a molec- 
ular weight at least three times that of formaldehyde, and containing a 
variable quantity of absorbed water. When prepared by concentrating 
solutions of pure formaldehyde, it melts at about 150-160° C, dissolves 

1 Arbb. Kais. Gesundt, Amt., 1907, 27, 183; Jour. Soc. Chem. Ind., 1907, 1294. 



576 ORGANIC SUBSTANCES 

to the extent of 20 to 30 per cent in water at 18° C, is insoluble in ether 
and alcohol, is not altered by boiling with water, and forms an addition- 
compound with sodium sulphite. a-Polyoxymethylene, (CH 2 0)w, is 
obtained by the addition of 1 volume of concentrated sulphuric acid to 
10 volumes of a pure aqueous solution of formaldehyde. It forms ill- 
defined crystals which melt at 163-168° C. when heated in a sealed tube, 
but are volatilized without melting when heated in an open tube. It is 
soluble to the extent of 11 per cent in water at 18-25° C, is insoluble in 
alcohol and ether, and forms a compound with sodium sulphite. Its 
vapors at 189° C. are composed of single CH 2 0-mols. /3-Polyoxymethy- 
lene is precipitated from a pure aqueous solution of formaldehyde by 
addition of .4 volume of concentrated sulphuric acid. It is crystalline, 
melts at 163-168° C. when heated in a sealed tube, is soluble to the extent 
of 3.3 per cent in water at 18° C, and up to 4 per cent in water at 25° C, 
and is insoluble in alcohol and ether. Its vapor density is 32 at 184° C. 
and increases slowly with rising temperature. It forms a compound 
with sodium sulphite, and when heated at 100° C. is converted into the 
7-modification. 7-Polyoxymethylene — On addition of .4 volume of sul- 
phuric acid to formaline (a solution of formaldehyde containing methyl 
alcohol), 7-polyoxymethylene is precipitated along with the correspond- 
ing jS-compound, and is freed from the latter by treatment with sodium 
sulphite solution. It is distinctly crystalline and melts at 163-165° C. 
It dissolves in water at 18-25° C. to the extent of about .1 gram in 100 
mils, and is insoluble in alcohol and ether. It does not react with sodium 
sulphite. At 184 and 198° C, its vapors contain polymerized molecules 
together with simple CEkO-mols.; the proportion of the former increases 
with rising pressure and decreases with rising temperature, the vapor 
densities at the temperatures given are 40 and 60 respectively. On boil- 
ing with water, 7-polyoxymethylene is converted into the 5-modification. 
5-Polyoxymethylene, obtained by prolonged boiling of the 7-compound 
with water, forms ill-defined crystals, the melting-point (169-170° C. 
in a sealed tube) of which is lowered by even traces of impurities. This 
modification also melts when heated in an open tube, whereas all of the 
others are volatilized below the melting-point. It is insoluble in alcohol 
and ether and nearly so in water. Its vapor density slowly decreases 
between 190 and 240° C; at these temperatures the vapors consist of 
highly polymerized molecules which split up only very slowly into simpler 
ones. The compound does not ( react with sodium sulphite. a-Trioxy- 
methylene, C3H6O3, is formed by sublimimg polyoxymethylene and 
collecting the sublimate in water. Commercial " trioxymethylene " 
(/3+ 7-polyoxymethylene, or 7-polyoxymethylene) was sublimed by heat- 
ing in a glass retort in a slow current of nitrogen, and the sublimate was 
collected in a receiver containing a small quantity of water, and cooled 



ALDEHYDES AND KETONES 577 

by ice. The distillate was submitted to fractional distillation, and the 
crystals which separated from the earlier fractions were purified by recrys- 
tallization from ether, or by sublimation in closed tubes. 

a-Trioxymethylene obtained in this way forms colorless needles or 
strongly refracting prisms, which are tough and soft, and melt at 63-64° 
when heated in closed tube. It boils at 114.5° C. at 759 mm., but is 
very volatile even at the ordinary temperature. It is soluble to the 
extent of 17.2 grams in 100 mils of water at 18° and 21.1 grams in 100 
mils at 25° C; it is easily soluble in alcohol, ether, methyl alcohol, ace- 
tone, chloroform, carbon tetrachloride, carbon bisulphide, and benzene, 
and soluble with difficulty in petroleum ether. It is probably a cyclic 
compound, as unlike the other polyoxymethylenes, it does not respond 
to the usual reactions for aldehydes or ketones; with sodium sulphite it 
does not react either in alkaline or acid solution. It exhibits a constant 
vapor pressure and vapor density. 

Paraformaldelryde differs from a-polyoxymethylene chiefly by its 
amorphous condition and its content of adsorbed water, and by the proper- 
ties depending upon these factors. Paraformaldehyde and a, /3, y and 5 
polyoxymethylenes all exhibit a tendency, decreasing in the order given, 
to split off formaldehyde as a gas or in aqueous solution; the aqueous 
solutions of these compounds do not differ from those of formaldehyde. 

Paraformaldehyde or trioxymethylene with formamide or acetamide 
gives compounds of the type R : NHCH2OH, used as antiseptics and 
uric acid solvents. 

E. Rust x has modified the hydrogen peroxide method in such a way 
as to render it available for the determination of formaldehyde in tablets 
and pastiles containing trioxymethylene. A funnel is placed in the mouth 
of a 250-mil conical flask, and 19-20 grams of the powdered substance 
weighed into it from a tube. The substance is washed down into the 
flask with 70 mils of N/1 sodium hydroxide delivered from a burette 
and dissolved. Then 9-10 grams of neutral 30 per cent hydrogen per- 
oxide are added at first in small portions and cautiously so as to avoid 
heating and filtering, and then more rapidly. After two hours the con- 
tents of the flask are heated cautiously to boiling and boiled to destroy 
the excess of peroxide. The funnel is now rinsed into the flask, a drop 
or two of phenolphthalein added and the liquid titrated with N/1 acid 
to very slight excess and then titrated back with N/1 alkali. Any required 
acidity or alkalinity of the substance must be tested for and if found 
titrated and allowed for. 

1 Z. angew. Chem., 1906, 19, 138. 



578 ORGANIC SUBSTANCES 



FORMALDEHYDE DERIVATIVES AND COMPOUNDS 

There have appeared on the market a number of compounds of for- 
maldehyde with various substances, among which may be mentioned 
condensation products with nucleinic acids, tannins, and tannin-like 
substances or their derivatives which claim antiseptic and astringent 
properties without the irritating effects of the formaldehyde, phenols, 
carbo-hydrates, starch, malt-extract, etc. Many of these are patented 
and sold with great claims for their therapeutic effects, and while some are 
true compounds, others are simply mixtures probably holding the formal- 
dehyde in absorption, or as the polymerized form from which the gas is 
regenerated under suitable conditions. These uncertain substances may 
furnish material for endless controversy in patent litigation and thera- 
peutical opinion. 

Methylal 

Methylal, CH 2 (OCH3)2, may be obtained by boiling aqueous formal- 
dehyde with methyl alcohol and a little sulphuric acid, but it is usually 
prepared by oxidizing methyl alcohol with manganese dioxide and sul- 
phuric acid. It is a pleasant-smelling liquid, specific gravity .855 at 15° 
C, boiling 42°, readily soluble in water, alcohol, and oils, and when dis- 
tilled with sulphuric acid is resolved into methyl alcohol and formaldehyde. 
It is used as a soporific administered in syrup or water, also injected in 
10 per cent solution, and is used locally in liniments or ointments as a 
local anesthetic. 

Amyloform 

A condensation product of formaldehyde and starch, white, odorless 
powder, insoluble in ordinary solvents and possessing antiseptic properties. 
It is used as a substitute for iodoform. 

Formaldehyde Acetate 

Methylene diacetate, CH 2 (C2H 3 02)2, is a heavy colorless liquid, boil- 
ing 170° C, soluble in alcohol and in water with decomposition. It has 
antiseptic properties. It is prepared by the action of methylene iodide 
on silver acetate. 

Glutol-Schleich 

Glutol-Schleich or Formalin Gelatin, is a chemical combination of 
gelatin and formaldehyde. 

It is a white odorless powder, insoluble in water under ordinary con- 
ditions, but dissolved when heated with water under pressure, the solu- 






ALDEHYDES AND KETONES 579 

tion thus produced gelatinizing on cooling. It is not changed by the 
action of acids, but is slowly decomposed in contact with living cells. 
It is to be used as an antiseptic dressing. 

Formicin 

Formicin is formaldehyde-acetamide, CHsCO-NH-.CEk-OH, a 
molecular compound of formaldehyde and acetamide. 

It is a slightly yellowish, thick, syrupy liquid, having a faint, formal- 
dehyde-like odor and a slightly acid, bitter taste. The specific gravity 
should be between 1.14 and 1.18 at 20° C. Formicin is soluble in water, 
alcohol, chloroform, and glycerin; it is nearly insoluble in ether. An 
aqueous solution (1 to 10) has an acid reaction on litmus. 

At 115° C. to 120° C. formicin dissociates. If 1 mil of an aqueous 
solution of formicin (1 to 10) is mixed with 1 mil of a mixture composed 
of equal volumes of stronger ammonia water, potassium hydroxide test 
solution and silver nitrate test solution, no immediate darkening should 
take place; but if the mixture is allowed to stand for some time, or is 
warmed, darkening occurs, due to the separation of metallic silver. 

Solutions of formicin liberate formaldehyde gradually at body tem- 
perature, and thus exert an antiseptic action. 

Fortoin — Methylene-Dicotoin 

Fortoin, CEkCCuHnO^, is a condensation product of cotoin and 
formaldehyde. 

Fortoin forms yellow, needle-shaped, tasteless crystals, melting at 
211° to 213° C. It is insoluble in water, sparingly soluble in alcohol, 
ether, or benzol, but freely soluble in dilute alkalies, acetone, or chloro- 
form. It dissolves in cold concentrated sulphuric acid with an orange 
color, and on warming the solution becomes ruby red. 

It is used as an antidiarrheic in acute and chronic intestinal catarrh 
and in obstinate diarrheas. 

Formaloin 

This product is a yellow, amorphous, tasteless powder soluble in 
alkalies, with difficulty in alcohol and insoluble in water. It is a con- 
densation product of formaldehyde and aloin and it is used for the same 
purposes as aloin. 

Forman 

This is a colorless, unstable oily liquid, readily decomposed by water 
or moist air, prepared by the action of formaldehyde on menthol in the 
presence of hydrochloric acid gas. Chemically it is chlormethylmenthyl 



580 ORGANIC SUBSTANCES 

ester, CioHigOCH^-Cl. It is soluble in oils and is used in catarrhal affec- 
tions either as an inhalant or on absorbent cotton. 

Formopyrin 

Methylenediantipyrin, (CnHnN20)2=CH2, prepared with formal- 
dehyde and antipyrin, forms colorless crystals, melting 176-177°, soluble in 
alcohol and almost insoluble in water. 

Ichthoform 

This product is prepared from formaldehyde and ichthyol, and is a 
dark-brown, practically odorless and tasteless powder, permanent and 
generally insoluble. 

Empyroform 

Empyroform is a condensation of birch tar and formaldehyde. 

According to the patent specifications birch tar is boiled with formal- 
dehyde solution and the hot liquid poured into hydrochloric acid. When 
cold, the solid mass is collected and washed until free from acid. 

It is a grayish-brown, almost odorless powder, insoluble in water, but 
soluble in acetone and chloroform. 

Empyroform is an antipruritic, sedative, and desiccant. 

Soap solutions containing formaldehyde are marketed under the name 
" Veroform." 

Resorcinoform 

This product results from the reaction of resorcinol and formaldehyde 
in the presence of hydrochloric acid, and is an amorphous currant-red 
powder with antiseptic properties. 

Hexamethylenetetramine, (CH 2 ) 6 N 4 

This body should strictly be taken up with the amines, but it is more 
conveniently discussed at this point as it is a derivative of formaldehyde. 
It results from the reaction of ammonia with formaldehyde. 

6CHOH+4NH 3 = (CH 2 ) 6 N+6H 2 

It is official in our Pharmacopoeia, and is sold under its chemical 
name and by a number of trade names associated with the firms exploiting 
it including aminoform, cystamin, cystogen, formin, uritone, urotropin, etc. 

It occurs in the form of colorless, lustrous, odorless crystals, readily 
soluble in water and alcohol and slightly in ether. The aqueous solution 



ALDEHYDES AND KETONES 581 

is alkaline. It sublimes at 263° C. without melting and with partial decom- 
position. It is precipitated by Mayer's reagent, mercuric chloride, tannin, 
bromin, . and other alkaloidal reagents. Bromin produces a brick-red 
precipitate, CeH^^Br-i, which on drying becomes yellow and is converted 
to the dibromide melting slightly below 200° C. 

One-tenth gram of the solid substance with .1 gram salicylic acid 
and 5 mils sulphuric acid gives a carmine-red color on warming. 

In the general scheme of qualitative analysis this body will remain 
in the aqueous solution through both of the acid and alkaline shake-outs. 
If a small portion of the solution which has been subjected to the regular 
treatment, is removed and acidulated, and if still found to give a marked 
precipitate with Mayer's reagent, the presence of hexamethylenetetra- 
mine may be suspected The solution should then be made strongly alka- 
line with sodium hydroxide and boiled until all the ammonia is dispelled, 
the hexamethylenetetramine being unaffected; it is then made acid with 
sulphuric acid and boiled again, preferably first under a reflux and then 
partly distilled, the distillate being tested for formaldehyde. The acid 
liquor is then treated with an excess of sodium hydroxide and boiled and 
if ammonia is now obtained the presence of the compound suspected is 
established. 

Puckner and Hilpert * use this method for estimating the substance. 
The liquid is first boiled with strong caustic alkali by which it is unaffected 
until all the liberated ammonia is driven off, then boiled with acid and 
finally with alkali, collecting the distillate in a known amount of standard 
acid and titrating back with alkali as in a Kjeldahl nitrogen determination. 

Hexamethylenetetramine may also be determined by precipitating it 
from acetic acid solution by mercuric chloride which yields the compound, 
C6H12N4 • 2HgCl2, this is washed with water containing mercuric chloride, 
dissolved in concentrated sodium chloride solution, the mercury precipi- 
tated by potassium hydroxide, filtered, the filtrate acidulated with sul- 
phuric acid and the regular Kjeldahl combustion and distillation prose- 
cuted. This method has been advanced by Schroter 2 for determining 
the body in urine. 



EVALUATION OF HEXAMETHYLENETETRAMINE TABLETS. W. O EMERY 

Reagents : 

A. Modified Nessler's Reagent, involving: 

(a) Solution of 10 grams HgCk, 30 grams KI and 5 grams acacia 

in 200 mils water, filtered through a pledget of cotton, and 
(6) Solution of 15 grams NaOH in 100 mils water. 
1 J. Amer. Chem. Soc, 1908, 30, 1471. 2 Arch. exp. Path. Pharm., 64, 161. 



582 ORGANIC SUBSTANCES 

B. Tenth normal iodin. 

C. Twentieth normal thiosulphate. 

Ascertain the weight of 20 or more tablets, triturate in a mortar to a 
fine powder and keep in a small capsule tightly closed with a cork or glass 
stopper. Weigh out .5 gram of the powdered product on a metal scoop 
or watch-glass, transfer with sufficient water to a round-bottom flask, 
add additional water to a total volume of 100 mils and finally 25 mils 
10 per cent HCL Connect with a reflux condenser (preferably of the worm 
type) and boil gently fifteen minutes, then after cooling wash-out con- 
denser tube with a little distilled water and transfer contents of flask 
quantitatively to a graduated 250-mil flask, finally diluting to the mark 
with water. 

With a pipette withdraw 10 mils (containing in the case of a pure prod- 
uct the elements of .02 grams C6H12N4) of the solution so prepared to 
a 200-mil Erlenmeyer containing a mixture (chilled in ice water if avail- 
able) of 20 mils reagent A (a) and 10 mils reagent A (b), wash down neck 
of container with a jet of water from the wash bottle and allow to stand 
at least one minute. Now add 10 mils 40 per cent acetic acid in such 
manner that the inside of neck is completely washed by the reagent, mix 
quickly and thoroughly by rotating and tilting flask, and immediately 
run in from a burette 20 mils of B, then titrate with C (adding 5-10 drops 
starch solution toward the end of the operation) to the disappearance 
of the blue coloration. The final color of the solution is a pale straw- 
green. If preferred, the end-point may be determined on the reappear- 
ance of a faint blue coloration, induced by the addition of further iodin. 

The reaction taking place between formaldehyde and potassium mer- 
curic iodide in the presence of caustic alkali is given in the equation : 

CH 2 0+K2Hgl4+3KOH = Hg+HC02K+4KI+2H 2 

In carrying out the method proper, unusual care is necessary in add- 
ing and mixing the several reagents with the preceding menstruum so 
that uniform solution shall result. This is effected by judicious rotation 
and tilting of flask, and at certain points also by washing down the neck 
of container with a jet of water. Addition of iodin should follow acidifi- 
cation with the greatest possible dispatch, on account of the fact that 
long standing of the mixture in the presence of free acetic acid invariably 
leads to low values for hexamethylenetetramine, due apparently to partial 
solution of colloidal mercury. The primary chilling of Nessler's reagent 
is advocated in order to minimize to the utmost any tendency toward 
secondary reactions, as also to avoid possible loss of iodin through undue 
increase in temperature on acidifying with acetic acid. 

Since the standard iodin (reagent B), employed has twice the strength 
of the thiosulphate (reagent C) , and 1 mil tenth normal iodin is equivalent 



ALDEHYDES AND KETONES 583 

to .001167 gram hexamethylenetetramine, the quantity of this product 
in the aliquot under examination is readily calculated from the expression : 

^-^N 0.001167 

in which H = number of mils reagent C equivalent to 20 mils reagent B, 
1 = number mils reagent C required to offset the unexpended iodin, and 
N= normality of reagent B. 

Derivati/es and Compounds of Hexamethylenetetramine 

There are many substances on the market claiming to be derivatives 
of hexamethylenetetramine, some of which are protected by patent. Some 
of these are claimed to be compounds with boric, citric, and other acids, 
with guaiacol and various phenols, with acid salts, sulphonic acid, etc. 
With certain compounds, simple treatment with chloroform is sufficient 
to remove the hexamethylenetetramine unchanged, and it is evident that 
the claim of possessing a new body is in some cases entirely unfounded. 

It is claimed that stable solutions of mercury and hexamethylenetetra- 
mine can be obtained by mixing the mercuric compound with a soluble 
albumin or the sodium salt of casein or an albuminate, and stirring into 
a large excess of 5 per cent soap solution. 

Hetralin 

Resorcinol-hexamethylenetetramine forms white crystalline needles, 
soluble in alcohol and water and decomposing above 160°. It is recom- 
mended as a diuretic and used in gonorrheal affections. 

Hexal 
Hexal is hexamethyleneamine salicylsulphonic acid, 
(CH 2 ) 6 N 4 • C 6 H 3 (OH)COOH ■ HS0 3 . 

It is a white, odorless, crystalline powder, readily soluble in water, 
slightly soluble in alcohol and difficultly soluble in ether, having an acid 
taste. 

A dilute aqueous solution of hexal gives a violet color with ferric 
chloride, a white precipitate with aqueous albumin solution, and an orange- 
colored precipitate with bromin water. 

With the exception of the tannic acid test, hexal responds to the identity 
tests of the U. S. Pharmacopoeia for hexamethylenemine. 

If .1 to .2 gram hexal is moderately heated with 5 mils concentrated 
sulphuric acid, a carmine-red color will be produced. 



584 ORGANIC SUBSTANCES 

Hexal is claimed to be useful in chronic inflammations of the bladder 
and in urethritis. 

Hexamethylenamine Methylenecitrate — Helmitol 

Hexamethylenamine methylenecitrate, CeHgOyCC^^N/t, is a com- 
pound of hexamethylenamine with anhydromethylenecitric acid. 

It is a white, crystalline powder, melting with decomposition at 165 
to 175° C, having an agreeable, acidulous taste and acid reaction. It is 
soluble in about 10 parts of water, but almost insoluble in alcohol and ether. 
By dilute acids and more easily by alkalies it is decomposed with the 
liberation of formaldehyde. On addition of 1 per cent solution of phloro- 
glucin to a solution of hexamethylenamine methylenecitrate, followed 
by sodium hydroxide, the intense rose-red color characteristic of the liber- 
ated formaldehyde is developed. 

It is used in cystitis, pyelitis, prostatic diseases, and urethritis. 

Saliformin 

Hexamethylenamine salicylate, (C^e^CelLrOH'COOH, is a weak 
salt of hexamethylenamine and salicylic acid. 

It is a white, crystalline powder, having an acidulous and disagree- 
able taste, readily soluble in water or alcohol. 

It is soluble in cold sulphuric acid without color, becoming crimson 
on heating. Its aqueous solution is colored deep green by copper sul- 
phate, violet by ferric chloride, and forms a yellow precipitate with bromin. 

It is decomposed with basic substances (soluble hydroxides, carbonates, 
etc.) and by strong acids. It is incompatible with salts of iron and other 
metals which form insoluble compounds with salicylates. 

It is said to be useful in cystitis, lithiasis, and bacterial affections of 
the urinary passages, also in gout, etc. 

Tannopin — Hexamethylen-tetramine Tannin — Tannon 

Tannopin, (Ci4Hi O 9 )3 • (CH 2 )eN4, is a condensation product of tannin 
with hexamethylenamine. 

It is a fine, fawn-colored and tasteless, nonhygroscopic powder, con- 
taining 87 per cent of tannin and 13 per cent of hexamethylenamine. 
It is insoluble in water, weak acids, alcohol, chloroform, or ether, but 
slowly soluble in dilute alkalies. On heating dry tannopin, it swells and 
gives off the odor of formaldehyde. The odor of formaldehyde is also 
developed on heating tannopin with dilute sulphuric or hydrochloric 
acid, while on boiling with sodium hydroxide solution it splits off ammonia. 
The clear aqueous filtrate from tannopin does not give a reaction with 
ferric chloride. 



ALDEHYDES AND KETONES 585 

Tannopin has an astringent and antiseptic action in the intestine; it 
passes unchanged through the stomach, but being gradually decomposed 
by alkalies, it becomes effective in the intestinal tract, exerting the action 
of its two components. 

Urystamine is probably a mixture of Hthium benzoate and hexamethyl- 
enetetramine. 

Thial 

Hexamethylenamine oxymethylsulphonate is a white odorless pow- 
der, easily soluble in water and used as an antiseptic. 

Bromalin 

Hexamethylenetetramine bromethylate, C6Hi2N4C2H 5 Br. Forms 
colorless crystals, melting 200°, soluble in water and used as a nerve 
sedative. It is claimed that it causes no brominism. 

Iodoformin 

Iodoformin is claimed to be a compound of hexamethylenamine and 
iodoform containing 75 per cent of iodoform. It is insoluble in water 
and is used for the same purposes as iodoform. 

Iodoformal, CeH^NQHoICHsI 

Iodoformal is obtained by the action of ethyl iodide on iodoformin. 
It is lemon-yellow odorless powder insoluble in water. 

ACETALDEHYDE, CH 3 CHO 

Acetaldehyde is a colorless, mobile, volatile liquid, specific gravity 
.790 at 15°, boiling 20-21°. It has a peculiar penetrating and suffocating 
odor, and mixes with water, alcohol, and ether in all proportions. It is 
slowly oxidized to acetic acid on exposure to air, has powerful reducing 
properties, and on treatment with reducing agents is converted to ethyl 
alcohol. With hydroxjdamine it forms a crystalline oxime, and when 
shaken with a concentrated solution of sodium bisulphite, the crystalline 
addition product separates. It combines directly with diy ammonia, 
producing a colorless crystalline substance aldehyde ammonia, which is 
decomposed by acids. When warmed with caustic alkalies it is converted 
into a brown substance called aldehyde resin. 

Three well-defined polymerides are known — aldol, paraldehyde, and 
metaldehyde. Aldol, CH 3 CH(OH)CH 2 CHO, is produced by the action 
of dilute hydrochloric acid or zinc chloride at ordinary temperatures. It 
is a colorless, odorless liquid, miscible with water, and shows all the ordi- 



586 ORGANIC SUBSTANCES 

nary properties of an aldehyde. It can be distilled unchanged under 
reduced pressure, but when distilled under ordinary pressure, or when 
treated with dehydrating agents it is converted into water and croton- 
aldehyde, CH 3 CH = CH-CHO. Paraldehyde, (C 2 H40) 3 , results when 
a drop of concentrated sulphuric acid is added to acetaldehyde. It is a 
colorless, pleasant-smelling liquid, specific gravity .995-. 998 at 15°, boil- 
ing 121-125° and solidifying in the cold. It is soluble in water, alcohol, 
ether, chloroform, and oils. It shows none of the ordinary properties 
of an aldehyde and its construction may be represented by the formula: 

O-CH— CH 3 

ch 3 — ch/ No 

O-CH— CH 3 

It is used as a stimulant, hypnotic, and antispasmodic, being employed 
for insomnia, and as an antidote for morphin poisoning. It is sometimes 
dispensed mixed with a fixed edible oil. 

Metaldehyde, (C 2 H£0)n, is produced by the action of acids at low 
temperatures. It crystallizes in colorless needles insoluble in water, is sub- 
limable without change, but on prolonged heating or by distilling with 
acids it is converted into acetaldehyde. 

S. S. Sadtler 1 has proposed a method for determining aldehydes 
based on the reaction with sodium sulphite whereby sodium hydroxide 
is liberated and titrated. For the determination of citral in lemon oil, 
from 5 to 10 grams of the sample are made neutral if necessary, treated 
with 25 to 50 mils of 20 per cent solution of sodium sulphite and neutral- 
ized with N/2 hydrochloric acid, using rosolic acid. The red color due 
to the free alkali is discharged by the acid, and the mixture kept hot and 
well agitated the titration with acid being continued as long as the color 
is reformed. The reaction is complete in one-half hour. 

C 9 Hi 5 COH+2H 2 0+2Na 2 S0 3 = C 9 Hi 7 COH(NaS0 3 ) 2 +2NaOH 

The reaction is available for the determination of vanillin, piperonal, 
and other aldehydes. The phenolic hydroxy 1 of the vanillin is neutral- 
ized by alkali, using rosolic acid, then sodium sulphite added and the 
titration with acid performed in the hot solution. The alkalinity of the 
sulphite must be determined and allowed for. Sadtler states that the 
reaction is complete and immediate with the fatty aldehydes. It will 
detect minute quantities of formaldehyde and is of value in detecting 
acetaldehyde in grain alcohol, and acetone in methyl alcohol. This 
procedure can be used for the determining acetaldehyde in the presence • 
1 J. Frank. Inst., 1904, 157, 231. 



ALDEHYDES AND KETONES 587 

of paraldehyde, first neutralizing the latter. Richter 1 has worked out 
the details which are as follows: Ten grams are shaken with 100 mils 
water, phenolphthalein added, and then N/1 potassium hydroxide until 
a pink color is obtained; 20 mils of sulphite solution (25 grams — 100 mils) 
are added and the liquid titrated with N/1 hydrochloric acid. A blank 
is run with 100 mils water and 20 mils of the reagent. Richter says that 
good commercial specimens of paraldehyde show less than 1 per cent 
of acetaldehyde, and if kept in full-stoppered bottles away from the light 
there is no need of any serious contamination. 



CHLORAL AND CHLORAL HYDRATE 

Chloral, CCI3CHO, is by far the most important derivative of acetal- 
dehyde from a medicinal point of view, and consequently to the analyst 
in this field. 

Chloral is not prepared by the direct action of chlorine on acetaldehyde, 
but is made from alcohol. The reaction is complicated, but chloral 

/OCsHs 

alcoholate is formed C-C13-CH , and on distilling this with sul- 

\)H 

phuric acid, chloral is obtained. It is purified by conversion to the hydrate 
and on distilling again with acid, the pure chloral results. Chloral with 
an equivalent amount of absolute alcohol gives chloral alcoholate, melting 
48°, boiling 113-114°. 

It is a heavy, oily-liquid, specific gravity 1.50, boiling 95-97°, with a 
penetrating and irritating odor, insoluble in water, but uniting with it. 
In chemical properties it closely resembles acetaldehyde, having strong 
reducing properties, and combining directly with ammonia, sodium 
bisulphite, etc. It is converted on oxidation to trichloracetic acid. With 
small quantities of acid it is converted into a white amorphous modifica- 
tion called metachloral. When boiled with potassium hydroxide it is 
decomposed into chloroform and potassium formate. It gives the well- 
known carbylamine reaction when warmed with potash and anilin. 

Chloral hydrate is a hypnotic, and has long been used as a constituent 
of " Knock-out " drops. In medicine it is valuable on account of its 
hypnotic properties. It is used in acute fevers, cerebral congestions, 
inflammations, mania, delirium tremens, croup, insomnia, tetanus, strych- 
nin, and cocain poisoning, chorea, and convulsions, and should be looked 
for in preparations intended for these disorders. Externally it is employed 
in alleviating foul sores, irritating ulcers, and in remedies for destroying 
parasites. 

1 Pharm. Zeit., 1912, 125. 



588 ORGANIC SUBSTANCES 

It will be found usually in the form of syrups or elixirs, and often 
combined with bromides, Hyoscyamus, and Cannabis indica. In dan- 
druff removers it occurs in conduction with resorcinol. To a limited extent 
it is dispensed in a compressed tablet or in capsule form. 

Chloral and its derivatives are included in the list of inhibited drugs, 
and the label of a preparation containing them is required to bear a state- 
ment of the quantity present. 

When chloral is poured into water the oily mass is soon changed to 
colorless crystals of chloral hydrate, CCl3CH(OH)2, which is strictly 
speaking a chlorinated diatomic alcohol. This is the form in which 
chloral appears on the market. It has a peculiar characteristic odor, 
melts at 57-58° C, boils 97°, is readily soluble in water, alcohol, and the 
ordinary organic solvents including petroleum ether, in fixed and volatile, 
and is decomposed on distillation with sulphuric acid, chloral passing 
over. It does not polymerize nor does it give the rosaniline reaction of 
aldehydes, in fact the general aldehyde properties due to the carbonyl 
group are no longer apparent, which is to be expected. It liquefies when 
triturated with an equal quantity of menthol, camphor, thymol, or phenol. 
An aqueous solution of chloral hydrate reduces ammoniacal silver oxide 
and Fehling's solution. It slowly volatilizes. A solution of chloral dis- 
solves morphin, quinin, and other alkaloids. The liquefied product solidi- 
fies to a crystalline mass between 35 and 50°. It does not give the iodo- 
form reaction and is not acted upon when gently heated with nitric acid 
of specific gravity 1.2. 

Chloral alcoholate differs essentially from chloral hydrate and is not 
readily soluble in water, gives the iodoform test and is acted upon by 
nitric acid, specific gravity 1.2. 

A solution of pyrogallol in 66 per cent sulphuric acid gives a blue 
color when gently warmed with chloral, and ruby color with butylchloral, 
and a more or less violet to blue color with mixtures. On adding a large 
amount of water the blue color changes to yellowish and the ruby to violet. 

In the general scheme of analysis chloral hydrate will appear on shak- 
ing out the acid solution with petroleum ether, and will be entirely removed 
in the next or ether fraction. The residue left on evaporating the solvent 
will be a colorless, syrupy liquid which will finally crystallize unless there is 
too much water present. This residue will have the characteristic odor 
of the substance, will give the carbylamine reaction and an aqueous solu- 
tion will reduce ammoniacal silver oxide and Fehling's solution. Butyl- 
chloral hydrate is much more difficultly soluble in water than chloral 
hydrate and has a melting-point of 78°, does not give chloroform on treat- 
ment with alkali and reacts differently with pyrogallol. 

Some little care may be necessary to distinguish between chloral and 
its amido compounds, and before leaving a chloral hydrate residue the 



ALDEHYDES AND KETONES 589 

analyst can well apply a few precautionary reactions. A small amount 
of the residue should be warmed with potassium hydroxide, and if there 
is no carbylamine odor it is almost certain that no amido substances are 
present. If, however, the odor is obtained it may indicate acetanilid, 
and in order to eliminate this contingency the residue should be heated in 
a small Erlenmeyer on the steam-bath with dilute sulphuric acid for an 
hour, not allowing the concentration to become great enough to produce 
charring, then diluted and shaken out several times with ether. The 
acid solution is warmed to drive off any dissolved ether and treated with 
bromin water which will throw out the tribromanilin bromide if anilin 
sulphate is present. The bromin compound must then be separated, 
washed, dried, and its melting-point determined. By this means any 
acetanilid will be hydrolyzed, and acetic acid and anilin sulphate produced, 
the latter remaining in the acid solution on shaking with ether to remove 
the chloral. Bromal hydrate can be distinguished from chloral hydrate, 
since it will give bromoform on warming with dilute alkalies. Bromoform 
boils 148-150° in contrast to chloroform, which boils 60-62°. 

Bromoform gives the carbylamine reaction, but when boiled with 
alcoholic potash it does not give a formate. 

CHBr3+3KOH+CYH 5 OH = 3KBr+CO+C2H4+3H 2 

Chloroform gives triethyl formate, which, on treatment with tartaric 
acid and distilled, yields formic acid. 

Chloral hydrate, on boiling with magnesium oxide and water, gives 
chloroform and magnesium formate. Trichloracetic acid yields chloro- 
form, but no formic acid. 

Most of the methods advanced for the quantitative estimation of 
chloral depend upon the decomposition of the substances with alkalies 
and separating and measuring the chloroform produced. If the sample 
under investigation is a solid, the chloral hydrate should be dissolved out 
of the excipient with ether, the solvent evaporated rapidly but without 
undue heating, and the residue washed with water into a small distilling 
flask, which is fitted with a tube bent twice at right angles, and running 
into a graduate accurately calibrated. Four to five grams of slacked 
lime are then added to the distilling flask, which is gently heated, so that 
the chloroform evolved will be cooled in the tube, and collected in the gradu- 
ate. After the bulk of the chloroform has come over, the heat is increased 
until about 10 mils of water have distilled, and then the volume of chloro- 
form is read off. The meniscus can be broken by adding a little potassium 
hydroxide. The volume of the chloroform multiplied by 1.84 gives the 
grams of anhydrous chloral or by 2.064 the amount of chloral hydrate. 

A liquid mixture may be examined in the same general way, first 
removing any alcohol that may be present by distillation, and then shaking 



590 ORGANIC SUBSTANCES 

out the chloral with ether from a slightly acid solution. If a previous 
qualitative test has shown little else than water and chloral, the solu- 
tion can be added directly to the distilling flask. 

If it is desired to assay a sample of chloral hydrate, a weighed sample 
is placed in a graduate and treated with strong potassium hydroxide solu- 
tion, keeping the mixture cool at first until the first violent reaction has 
ceased. The tube is then stoppered and shaken, and after two to three 
hours the volume of the chloroform determined. 

A residue of chloral hydrate can be titrated with alkali, using litmus 
as an indicator. It is dissolved in water and any free acid present neutral- 
ized with barium carbonate, the filtrate treated with a known excess of 
N/1 sodium hydroxide and titrated back with acid. One mil N/1 alkali 
= .1415 gram chloral or .1655 gram chloral hydrate. 

Chloral hydrate can also be determined by boiling with magnesium 
oxide and water under a reflux, whereby chloroform and magnesium form- 
ate result. The chloroform is then distilled, the aqueous solution acidi- 
fied with tartaric acid and the formic acid distilled with steam using the 
details and precautions prescribed on page 627, under the determination 
of formic acid. 

Self, 1 criticising the B. P. method of assaying chloral, recommends 
heating .3 gram of the sample with 1 gram aluminum powder or 2.5 grams 
zinc filings, 15 mils glacial acetic acid and 40 mils water for one-half hour 
under a reflux. The mixture is then filtered and after washing, the chlorine 
in the solution is determined. 

The detection of small quantities of chloral, especially in the presence 
of chloroform, bromoform, and trichloracetic acid, can be accomplished 
by dissolving the residue in water faintly acid with sulphuric acid, trans- 
ferring to a flask, adding a little zinc and closing the flask with cotton. 
When the evolution of hydrogen has ceased, the flask is warmed and the 
vapor escaping allowed to act on paper impregna/ted with sodium nitro- 
prusside and 5 per cent piperidin. A blue coloration indicates aldehyde 
formed by the reduction of the chloral. 

Trichlorethidene propenyl ether, CCl 3 CHO(OH)3C 3 H 5 

This ether is a condensation product of chloral and glycerin and is 
marketed in a glycerine solution under the name " Somnos." 

Dimethylethylcarbinol chloral, CoHsCCHs^COCHOHCCls 

This product is sold under the name of " Dormiol," either in a 50 per 
cent aqueous solution, or in globules or capsules in an oil medium. It 
is soluble in alcohol, ether, and chloroform, reduces ammoniacal silver 

1 Pharm. J., 1907, 79-4. 



ALDEHYDES AND KETONES 591 

oxide similarly to chloral, and on treatment with caustic alkali is decom- 
posed with a precipitation of chloroform. It is gradually broken down 
by simply warming its aqueous solution or on exposure to the light. 

Bromal, CBr 3 CHO 

Bromal is a heavy yellowish liquid, specific gravity 2.30 at 15°, boiling 
174° C, soluble in alcohol and ether, and forming the hydrate with water. 

Bromal Hydrate, CBr 3 CH(OH) 5 

This body is closely related to chloral hydrate, it forms white deli- 
quescent crystals having a similar odor to chloral hydrate. It melts 53° C. 
and is soluble in water, alcohol, ether, and chloroform. It is employed 
for the same purposes as chloral, but will seldom be encountered in prac- 
tice. 

On warming with alkali it yields bromoform and a formate. 

Butyl-chloral, CH 3 CHC1CC1 2 CH0 

Butyl-chloral is made by passing dry chlorine through acetaldehyde 
cooled to - 10° C. ; on fractional distillation of the product, the fraction 
boiling 163-165° C. is collected. It is a colorless, oily liquid, specific 
gravity 1.395 at 20° C, and soluble in alcohol, ether, and water. On 
oxidation with nitric acid it yields trichlorbutyric acid, melting about 60° 
and boiling 235-238°. 

Butyl-chloral Hydrate, CH 3 CHC1CC1 2 CH(0H) 2 

The hydrate results on adding water to butyl chloral. It occurs in 
crystalline micaceous scales of a pungent odor, melting 78°, readily solu- 
ble in alcohol, ether and glycerin, sparingly soluble in water and only 
slightly in chloroform. It does not yield chloroform when heated with 
alkalies or lime water. Its use is limited, but in general it is given for the 
same purposes as chloral. 

Chloralurethane, CCl 3 CH(OH)(NH)COOC 2 H 2 

This substance, also called uraline, ural, or uralium, is prepared by 
heating chloral with urethane (ethyl carbamate), CO(NH2)OC2H 5 , and 
then adding sucessively hydrochloric acid and acetic acid. It forms color- 
less crystals, melting 103°^ readily soluble in alcohol, water, and ether. 

Chloral formamide, CClsCHOHCONHo 

This product, also called " chloralamide," is official in our Pharmaco- 
poeia. It occurs as lustrous, colorless, odorless crystals, readily soluble in 



592 ORGANIC SUBSTANCES 

ordinary organic solvents, glycerin, and water, melting 114-115°. It is 
decomposed when heated in solution. 

It is used as a hypnotic and analgesic, and should be suspected in 
remedies for certain forms of neuralgia and sleeplessness accompanying 
headache. Its melting-point is very close to that of acetanilid. 

Chloralimide, CC1 3 CH = NH 

Chloralimide occurs in colorless, odorless crystals, melting 153°, 
readily soluble in alcohol, ether, chloroform, and oils and insoluble in 
water. It is employed for the same purposes as the preceding substance. 

Chloralose — Anhydroglucochloral, CgHnClsOe 

Chloralose results from the action of anhydrous chloral on glucose. It 
forms colorless crystals, melting 183°, soluble in alcohol and slightly in 
water. 

It is claimed that this body will produce sleep without affecting the 
heart and without cumulative tendency. 

Galactochloral 

This body probably resembling the former in composition, occurs in 
lustrous leaflets, soluble in alcohol and insoluble in water. 

Hypnal 

Hypnal is an equimolecular mixture of chloral hydrate and antipyrin, 
and melts 67° C. It is readily soluble in water. 

Viferral 

Viferral is prepared from chloral and pyridin, and is a white powder, 
readily soluble in warm water, but not in water acidulated with hydro- 
chloric acid. It melts 150-155°. It is similar to if not identical with 
the substance called " Poly chloral," which is apparently a polymerized 
chloral, and readily converted by water into chloral hydrate. 

Chloral Acetone Chloroform 

This substance is made by heating together equimolecular quantities 
of chloral and trichlortertiary butyl alcohol or chloretone. The resulting 
product melts 65° and may be sublimed unchanged. It possesses a faint 
odor and taste resembling camphor, sparingly soluble in cold water, and 
is decomposed by acids into its components. Just how intimately the 
separate bodies are combined is as yet uncertain. 



ALDEHYDES AND KETONES 593 

A solid polymeric form of chloral results when the oil is treated with 
anhydrous aluminum chloride. The resulting product is insoluble in 
alcohol, water, or acids, but dissolves in sodium carbonate solution. It 
gives chloroform on warming with alkali. 

Trichloracetic acid, CCI3COOH 

This substance would perhaps be more properly discussed under acids, 
but as it is in some respects a derivative of chloral, and in some of its 
chemical properties bears a resemblance to that body, it will be taken up 
now. 

It is obtained by oxidizing chloral with nitric acid, and on distillation 
the portion coming over at 195° is the pure acid. It boils at that tempera- 
ature, melts at 52-53° C, and forms deliquescent, colorless crystals, with 
a pungent, suffocating odor and freely soluble in water, alcohol, and ether. 
Hot alkalies decompose it into chloroform and a carbonate, chloral under 
similar conditions yielding chloroform and a formate. It will of course 
give the carbylamine reaction. 

Trichloracetic acid will be removed from an acid aqueous solution 
with ether, and may be recognized by its odor, boiling-point, and chemical 
properties. 

There are two other chloracetic acids, monochlor, melting 62° and 
boiling 185-187°, and dichlor, a liquid boiling 190-191°. Neither of them 
will give chloroform on treatment with alkali. 

All of the chloracetic acids are powerful escharotics, astringents, and 
hemostatics. The trichlor is the one generally used and will be found 
in wart and corn remedies, in liquids for local application in the nose 
and throat for the removal of growth, and for the removal of venereal 
growths, chancre, gleet, gonorrhea, etc., and for alleviating nose bleed. 

Trichlorbutyric acid, CH 3 CHC1CC1 2 C00H 

Trichlorbutyric acid is prepared from butylchloral by oxidation with 
nitric acid. It forms colorless needles, slightly soluble in water, melting 
above 60° and boiling 235-238° C. 

AROMATIC ALDEHYDES 

The aromatic aldehydes may be derived from the corresponding alco- 
hols by mild oxidation. Those with the carbonyl group attached to the 
nucleus differ in some particulars from those in which it is attached to 
the side chain, but in general their properties are similar, and those of 
the latter class resemble the aliphatic aldehydes very closely. Those 
with the aldehyde group in the nucleus do not reduce Fehling's solution, 



594 ORGANIC SUBSTANCES 

do not form addition products with ammonia, and when shaken with 
alkali from a corresponding alcohol and acid. 

Benzaldehyde, C 6 H 5 CHO 

Benzaldehyde is a representative of the type with the carbonyl in 
the nucleus. It was formerly obtained by the decomposition of amygdalin, 
a glucoside occurring in bitter almonds, but is now prepared synthetically. 

It is a colorless liquid, boiling 179°, specific gravity 1.05 at 15° and 
volatile with steam. It has a characteristic odor, is sparingly soluble 
in water, but readily in organic solvents. It is completely oxidized in 
alcoholic solution to benzoic acid, which furnishes a simple method for 
its determination. 

Benzaldehyde is the chief constituent of oil of bitter almonds and other 
oils distilled from similar fruits. It is also a constituent of Cherry Laurel 
Water and shares its reputation with hydrocyanic acid, with which it 
endeavors to strike an equihbrium as benzaldehyde cyanhydrin. 

Determination of Benzaldehyde, U. S. P. — Dissolve about 3 mils of 
freshly redistilled phenylhydrazine in 60 mils of alcohol and titrate 25 
mils of this solution, which must always be freshly prepared, with half- 
normal hydrochloric acid V. S., using methyl orange TVS. as indicator. 
To about 1 gram of the Oil of Bitter almond, accurately weighed, add 
25 mils of the phenylhydrazine solution just prepared and allow it to 
stand for thirty minutes. Add a drop of methyl orange T. S., and acidify 
the mixture by adding a measured excess of half -normal hydrochloric acid. 
Filter the mixture and wash the precipitate with small portions of dis- 
tilled water until the washings cease to redden blue litmus paper. Then 
titrate the excess of hydrochloric acid in the filtrate with half -normal 
potassium hydroxide V. S. and subtract the number of mils of the half- 
normal hydrochloric acid V. S. used in titrating the 25 mils of phenyl- 
hydrazine solution; the difference multiplied by .053 gives the weight of 
benzaldehyde. 

Method of Hortvet and West. — Measure 10 mils of the extract into a 
100-mil flask, add 10 mils of a 10 per cent sodium hydroxide solution and 
20 mils of a 3 per cent hydrogen peroxide solution, cover with a watch- 
glass and place on a water-oven. Oxidation begins almost immediately 
and should be continued from five to ten minutes after all odor of benzal- 
dehyde has disappeared, which usually requires from twenty to thirty 
minutes. If nitrobenzol be present, it will be indicated at this point by 
its odor. When the oxidation of the aldehyde is complete, remove the 
flask from the water-oven, transfer the contents to a separatory funnel, 
rinsing off the watch-glass, add 10 mils of a 20 per cent sulphuric acid 
solution, and cool the contents of the funnel to room temperature under 



ALDEHYDES AND KETONES 595 

the water tap. Extract the benzoic acid with three portions of 50, 30, 
and 20 mils of ether, respectively, wash the combined extracts in another 
separatory funnel with two portions of from 25 to 30 mils of distilled water, 
or until all the sulphuric acid is removed. Filter into a tared dish, wash 
with ether, allow to evaporate at room temperature, and finally dry over- 
night in a desiccator, and weigh. The per cent of benzaldehdye (B) is 
obtained from the weight of the acid (W) by the following formula: 

0.869X10XIT 
1.045 

If desired the benzoic acid may be titrated, and the benzaldehyde 
calculated from the amount of standard alkali required for neutralization. 
The process is as follows: Dissolve the benzoic acid obtained as above 
described, except that it need not be dried in a desiccator, in 95 per cent 
alcohol, made neutral to phenolphthalein with N/10 sodium hydroxide, 
dilute with an equal volume of water, and titrate with N/10 sodium hydro- 
oxide, using phenolphthalein as indicator. The per cent of benzaldehyde 
(B) is calculated from the mils of N/10 alkali (7) by the following 
formula: 

7X0.01061X10 



£= 



1.045 



Cinnamic Aldehyde, C 6 H 5 CH : CHCHO 

This aldehyde is the chief constituent of oils of cinnamon and cassia. 
It is a yellowish oil with a characteristic odor, boiling about 245° C. under 
ordinary pressure with partial decomposition or at 128-130° at 20 mm. 
pressure, readily soluble in all the organic solvents, from which it may 
be extracted by shaking with sodium bisulphite solution. It oxidizes 
gradually and samples which have stood for any length of time will con- 
tain free cinnamic acid. Oxidation with peroxide converts it to cinnamic 
acid with the simultaneous formation of a little benzoic. 

Estimation, U. S. P. Method. — Introduce 10 mils of the oil into a 
200-mil flask with a long graduated neck (cassia flask) by means of a 
pipette, add 50 mils of a saturated solution of sodium sulphite, which 
has been carefully rendered neutral to phenolphthalein by means of acetic 
acid, heat the mixture in a bath containing boiling water and shake the 
flask repeatedly, neutralizing the mixture from time to time by the addi- 
tion of a few drops of dilute acetic acid. When no coloration appears, 
upon the addition of a few more drops of phenolphthalein and heating 
for fifteen minutes, cool, and when the liquids have separated completely, 
add sufficient of the sodium sulphite solution to raise the lower limit of 
the oily layer within the graduated portion of the neck and note the volume 



596 ORGANIC SUBSTANCES 

of the residua] liquid. It shows not less than 80 per cent by volume, 
of cinnamic aldehyde. 

It is found that cinnamic aldehyde, both pure, and as it occurs in 
cinnamon and cassia oils, may be quantitatively precipitated in the form 
of semioxamazone : 

CeHs-CH : CH-CH : N-NHCO-CONHs, 

by treating an aqueous suspension with a solution of semioxamazide in 
hot water. 

About .10 gram of the aldehyde is emulsified by agitation with 100 
mils of water and treated with .25 to .35 gram of semioxamazide dissolved 
in 15 mils of hot water; the mixture is well shaken together, occasionally, 
for three hours, then allowed to stand for twenty-four hours. The crys- 
talline cinnamic-aldehyde semioxamazone is then collected on a tared 
Gooch filter, washed with cold water, dried at 105° C. for about four or 
five hours, then weighed. The weight of semioxamazone multiplied by 
the factor .6083 gives the amount of cinnamic aldehyde present. For 
the determination of the amount of aldehyde in cinnamon and cassia 
oils, from .15 to .2 gram is employed. 

To determine the amount of cinnamic aldehyde in cinnamon or cassia 
barks, from 5 to 8 grams of the finely ground material are distilled with 
steam, until about 400 mils of distillate have been collected. The volatile 
oil is extracted from the distillate by shaking out three or four times with 
ether, and after distilling off the ether, the oil is emulsified and treated 
with semioxamazide as described above. 

Salicylic Aldehyde, C 6 H 4 (OH)CHO 

O-hydroxybenzaldehyde, sometimes called " salicylous acid " may be 
obtained by oxidizing salicin with chromic acid. It possesses the proper- 
ties of a phenol and an aldehyde. It is a colorless oil with a penetrating 
odor, boiling 196°, specific gravity 1.165-1.172 at 15° C, somewhat soluble 
in water to which solution ferric chloride imparts a violet color, and dis- 
solving in all the ordinary organic solvents. 

Salicylic aldehyde occurs naturally in flowers of Spiraea ulmaria. 

The p- and ra-aldehydes are solids, melting 116° and 104° respectively. 

Salicylic aldehyde on treatment with sodium acetate and acetic anhy- 
dride is converted to coumarin, the odorous principle of tonka bean, 

Anisic aldehyde, C 6 H 4 (OCH s )CHO 

Anisic or p-methoxybenzaldehyde is obtained on oxidizing anethole, 
C6H4(OCH 3 )CH : CH : CH 3 , from oil of anise. It is a colorless oil with 
a penetrating odor boiling 248°. 



ALDEHYDES AND KETONES 597 



Cuminic Aldehyde, C 6 H 4 (CH 3 )2CHCHO 

Cuminic or paraisopropyl benzoic aldehyde, incorrectly called cuminol, 
is the constituent of oil of cumin, to which it owes its odor and more 
prominent properties, and also occurs in oil of Roman chamomile. 

It is a yellowish oil with a persistent odor, and acrid burning taste, 
specific gravity .972 at 13°, boiling 232° or at 109.5° under 13.5 mm., 
soluble in alcohol and ether. 



Vanillin, C 6 H 3 OH • OCH 3 CHO 4:3:1 

Methyl protocatechuic aldehyde or vanillin is one of the valuable con- 
stituents of vanilla beans, and also occurs in Siam benzoin and asafetida. 
It is not prepared in a commercial way from either of these sources, but 
from eugenol, an aromatic unsaturated phenol occurring in oil of cloves. 

It occurs in colorless prisms having an aromatic odor and a vanilla- 
like taste, melting 80-81°, boiling 285°, subliming when cautiously heated, 
slightly soluble in water and readily in the organic solvents. Its aqueous 
solution gives a blue color with ferric chloride. 

Vanillin possesses the characteristics of both a phenol and an aldehyde, 
and is therefore removed from its solution in organic solvents by both 
alkalies and sodium bisulphite. 

It is used to a limited extent in medicine as a tonic, stimulant, and 
aphrodisiac, and its presence is recognized without difficulty by its 
characteristic odor. 

Coumarin of course has an odor which simulates that of vanillin, but 
may be distinguished from the latter as it is not removed from its solution 
in ether by sodium hydroxide. 

Vanillin reduces ammoniacal silver oxide. When heated with dilute 
hydrochloric acid under pressure to 200° it yields protocatechuic aldehyde 
and methyl chloride. When fused with potash, protocatechuic acid 
results. 

On exposure in a moist or finely divided state it is oxidized to vanillic 
or methylprotocatechuic acid, melting 207°, which gives no color with 
ferric chloride. It yields vanillyl alcohol melting 115° on reduction. 

Vanillin gives a characteristic color when heated with hydrochloric acid 
and phloroglucinol. It gives a deep-bluish violet color when rubbed with 
resorcinol and hydrochloric acid. 

Vanillin as now found on the market is usually quite pure, but it was 
formerly contaminated with acetyl isoeugenol, due to incomplete purifica- 
tion, and it also was sophisticated by admixture with benzoic acid and 
acetanilid 



598 ORGANIC SUBSTANCES 

Folin's Method for Determining Vanillin. — Solutions Required: (1) An 
aqueous solution of pure vanillin to be used as a standard. This should 
be made of such a strength that 10 mils contains 1 mg. of vanillin. 

(2) The phosphotungstic-phosphomolybdic acid reagent, prepared as 
follows: To 100 grams pure sodium tungstate and 20 grams phosphomo- 
lybdic acid (free from nitrates and ammonium salts) add 100 grams 
syrupy phosphoric acid (containing 85 per cent H3PO4) and 700 mils 
water; boil over a free flame for 1| to 2 hours; then cool, filter if necessary, 
and make up with water to a volume of 1 liter. An equivalent amount 
of pure molybdic acid may be substituted for the phosphomolybdic 
acid. 

(3) A solution of pure sodium carbonate saturated at room temper- 
ature. 

(4) A solution containing 5 per cent basic and 5 per cent neutral lead 
acetate. 

Vanillin (and also other mono-, di-, and trihydric phenol compounds) 
when treated in acid solution with the phosphotungstic-phosphomolybdic 
reagent above described gives on the addition of an excess of sodium car- 
bonate a beautiful deep-blue color admirably suited for quantitative 
colorimetric work. 

Five mils of the vanilla extract to be examined are transferred by 
means of a pipette to a 100-mil volumetric flask and about 75 mils cold 
tap water are added: 4 mils of the lead acetate solution are then poured 
in and the mixture made up to volume with water. 

The contents of the flask are then rapidly filtered through a folded 
filter paper; and 5 mils of the filtrate are transferred by means of a pipette 
to a 50-mil volumetric flask. In another 50-mil volumetric flask is placed 
5 mils of the standard vanillin solution; then 5 mils of the phosphotungstic- 
phosphomolybdic reagent is added to each flask, the reagent being allowed 
to run down the neck of the flasks in order that any vanillin adhering 
thereto may be washed down. After shaking, the flasks are allowed to 
stand for five minutes and are then filled to the mark with saturated 
sodium carbonate solution. After inverting the flasks two or three times 
in order that the contents may become thoroughly mixed, they are allowed 
to stand for ten minutes, by which time the precipitation of sodium phos- 
phate is complete. The contents of the flasks are then rapidly filtered 
through a folded filter paper and the color of the resulting clear deep-blue 
solutions compared by means of a Dubosc colorimeter. The standard 
solution is best placed at 20 mm. as experiment has shown that the color 
produced by the amount of vanillin contained therein (1 mg. in 100 mils) 
is most accurately and easily read at this point. 

In this, as in all other colorimetric methods, a slight cloudiness of the 
solution to be read, by cutting off more light than the standard, gives 



ALDEHYDES AND KETONES 599 

a reading much too low, with correspondingly high results; consequently 
no solution should be read which is not absolutely clear after filtration. 

The calculation of the results is not complicated. When 5 mils of 
the solution (previously diluted 5 : 100) is taken, this corresponds to .25 
mil of the original solution. If 10 mils are taken they correspond to .5 
mil of the original. Since .5 mg. vanillin is used as a standard and with 
the standard set at 20 (mm.) .5X20/5= X where R is the colorimeter 
reading of the unknown and X is the amount of vanillin in mgs. present 
in the volume of the original extract used in the final color comparison; 
100 X divided by the volume of the extract taken expressed in mgs. gives 
the result in grams per 100 mils. 

Piperonal 
CHO 

\/\ 

CeHs >CH2 

NT 

This substance, which is chemically the methylene ester of proto- 
catechuic aldehyde, is also known as heliotropin. It may be obtained by 
the gradual addition of potassium permanganate to a solution of potassium 
piperate, obtained by the fusion of piperin, and forms white, shiny crys- 
tals with a pleasant characteristic odor of heliotropin, melting 37°, slightly 
soluble in water, readily in alcohol and ether. It does not keep well 
except in alcoholic solution. 

It is used medicinally as an antiseptic and antipyretic, and will be 
found in remedies for skin diseases and fevers. 

Piperonal is now made from safrole, 



C3H51 




by saponifying and then oxidizing with permanganate and sulphuric acid. 

When heated to 200° under pressure with dilute hydrochloric acid 
it gives protocatechuic aldehyde and carbon. 

Piperonal may be adulterate.d with vanillin and products formed dur- 
ing its manufacture. 

KETONES 

As medicinal agents the ketones of the aliphatic series have little 
importance, acetone is employed as a solvent and vehicle to some extent 
and methylisopropyl ketone has hypnotic properties. Of the aromatic 
ketones acetophenone and benzophenone with some of their derivatives, 



600 ORGANIC SUBSTANCES 

have attained considerable importance, and the cyclic ketone camphor is 
a valuable medicinal agent. 

In the aliphatic series the ketones form an homologous series isomeric 
with the aldehydes, and are closely related to them in all reactions affect- 
ing the carbonyl group, which is common to both classes. Ketones form 
crystalline compounds with bisulphite, and oximes with hydroxylamine, 
and also react with phenylhydrazine and hydrocyanic acid. They are 
produced by the oxidization of secondary alcohols. They differ markedly 
from the aldehydes on oxidation, for, while the aldehydes are oxidized 
with ease to an acid containing the same number of carbon atoms, the 
ketones are only acted upon by stronger oxidizing agents, and are broken 
up, yielding products containing a smaller number of carbon atoms. 
Ketones do not reduce ammoniacal silver, nor restore the color to fuchsin 
bisulphite, neither do they polymerize though they form condensation 
products under certain conditions. Futhermore they do not form addi- 
tion products with ammonia nor combine with alcohols to form acetals. 

The lower members of the ketone series are colorless, mobile, odorous, 
volatile liquids soluble in water, alcohol, and ether. As the number of 
carbon atoms increases, the boiling-point rises and the solubility in water 
decreases. The higher members are heavy solids. Ketones give the cor- 
responding secondary alcohols on reduction. A secondary alcohol is not 
the sole product of reduction, but is usually accompanied by varying 
quantities of pinacones, acetone for example yielding acetone pinacone, 
(CH 3 )2C(OH)-C(OH)(CH 3 )2. Pinacones on distillation with dilute sul- 
phuric acid, yield pinacolines, that from acetone pinacone is a colorless 
liquid boiling 100° and having a menthol-like odor. 

Ketones are acted on by phosphorus pentachloride with formation of 
dihalogen derivatives of paraffins. When treated with dehydrating agents 
they undergo a form of condensation with elimination of water, two or 
more molecules taking place in the reaction, thus acetone gives mesityl 
oxide, CeHioO, and phoron, C9H14O. 

Acetone, CH 3 COCH 3 

Acexone has a limited use in medicine as a mild alterative and anthel- 
mintic, and locally in certain forms of irritation where it is administered 
as a liniment. It is also used as a vehicle and does not have to be declared 
on the label. 

In liniments intended for local application it will be found combined 
with extracts and oils of arnica, calendula, turpentine, cade, and similar 
products, thujone, camphor, etc. Some of these mixtures are recommended 
as bactericides and for the absorption of calluses, tumors, goiter and 
like growths. 



ALDEHYDES AND KETONES 601 

Acetone is a colorless, mobile liquid, specific gravity .792 at 20° C, 
boiling 56-57° with a peculiar, characteristic ethereal odor, and miscible 
in all proportions with water, alcohol, ether, chloroform, and volatile 
oils. When shaken with concentrated sodium bisulphite, it forms a 
crystalline compound which is readily soluble in water but insoluble in 
alcohol, and decomposed by dilute acids or alkalies. It forms acejxixime 
with hydroxylamine, a crystalline substance melting 59° C. With phos- 
phorus pentachloride it yields beta-dichlorpropane, (CH^CC^. 

Acetone gives the iodoform reaction in the cold. It does not reduce 
ammoniacal silver, nor give the rosaniline test. 

WTien saturated with dry hydrogen chloride it yields mesityl oxide 
and phoron, and when distilled with concentrated sulphuric acid it yields 
mesitylene, a derivative of benzol. Mesityl oxide is a colorless oil, boiling 
130° C. with a menthol odor. Phoron is a colorless, crystalline solid 
melting 28°, and boiling 196°, with a pleasant aromatic odor. Both sub- 
stances are reverted to acetone on boiling with dilute sulphuric acid. 
Mesitylene 

CH 3 



CH3V /CH3 



is symmetrical trimethylbenzene, a colorless, mobile, fragrant liquid 
boiling 163°. 

When molecular proportions of acetone and chloroform or acetone 
and bromoform are treated with caustic alkalies, chloretone melting 
80-81° and brometone melting 167° are found respectively. Both of 
these substances are trichlor and tribrom derivatives of tertiary butyl 
alcohol. 

On chlorinating acetone, monochloracetone, CH3COCH2CI, is one of 
the products. It is a colorless, pungent liquid, specific gravity 1.162 at 
16°, boiling 105-106°, miscible with alcohol, ether, and chloroform and 
insoluble in water. 

For the detection of acetone, the distillate from a mixture should be 
employed, and if the distillate contains any essential oils they should be 
removed by shaking out with salt and petroleum ether, and the salt solu- 
tion again distilled. If acetone is present, the distillate will give a pre- 
cipitate of iodoform in the cold on adding a little sodium hydroxide and 
iodin solution. It will also give characteristic tests with salicylaldehyde 
and sodium nitroprusside. The former is carried out as follows: 10 mils 
of the liquid are treated with 1 gram of solid potassium hydroxide, and 
10 drops salicylaldehyde and warmed to 70° C. In presence of acetone 
a purple-red contact ring develops. If the hydroxide is all dissolved 



602 ORGANIC SUBSTANCES 

before the reagent is added, the liquid becomes yellow, reddish and purple- 
red 

The Nitroprusside Reaction. — Shake five drops of the ketone with 2 mils 
of cold water. If the substance does not dissolve completely, filter through 
a wet filter. Add to the clear solution two drops of a 1 per cent aqueous 
solution of sodium nitroprusside, and then two drops of sodium hydroxide 
solution (1 : 10). Without any unnecessary delay, carefully note the 
color, and then quickly divide the solution into two equal portions, a and 6, 
in small glass " weighing-tubes." To portion b add three drops of glacial 
acetic acid, and immediately note the color. Allow both solutions to 
stand for twenty minutes, and again carefully compare the color of each 
with the color standard. 

Many of the aldehydes as well as ketones give colorations in this test; 
but its most important practical application is its use as a convenient 
specific reaction for acetone and acetophenone. It distinguishes these 
ketones readily from all related ketones with which either is likely to be 
confused. 

In the case of acetone, portion a at first is orange, but changes to a 
clear yellow within twenty minutes. Portion b after the acidification 
with acetic acid is a red when viewed against a white background, with 
a very slight tendency to purple, that is most noticeable when the solu- 
tion is viewed by a strong transmitted light. This hue will be found 
unchanged at the end of twenty minutes, though its intensity will have 
fallen about one tint. The persistency of this hue in acetic-acid solution 
is the most characteristic part of the test when used to distinguish acetone 
from its homologues. 

In the case of acetophenone, the color of portion a is at first red with 
a very slight tendency to violet-red, just as in part b of the acetone test 
after acidification. This changes to yellow before the end of twenty 
minutes. Portion b upon acidification with acetic acid changes at once 
to a strong blue, whose hue is not materially changed at the end of twenty 
minutes, although it will have faded nearly one tint. 

The most characteristic part of the acetophenone test is the strong 
blue coloration of portion b. Homologues of acetophenone, CH 3 CO-R, 
like methyltolyl- and methylxylyl ketone, give pale violet or bluish color- 
ations. Fatty aromatic ketones, like ethyl-phenyl ketone, which contain 
no methyl radical in combination with CO * R, appear not to give any blue 
coloration at all. 

Sodium-nitroprusside solution does not keep very well, and should 
not be more than a few days old when used. 

Method for the Determination of Methyl Alcohol and Acetone in 
Drug Products. — A measured portion of the sample is diluted and filtered 
if deemed advisable and the whole or a convenient aliquot distilled into 



ALDEHYDES AND KETONES 603 

such a volume that the distillate shall contain not more than 30 per cent 
volatile matter other than water. 

If volatile oils are present, the sample, either before or after dis- 
tillation, is freed from them by one of the following methods : 

(a) Shake with magnesium carbonate and filter, taking precautions 
to avoid loss by evaporation. 

(6) Saturate with salt and shake with petroleum ether. Separate 
the aqueous layer and if necessary repeat once or twice with fresh petro- 
leum ether. Wash the successive or combined petroleum ether portions 
with saturated salt solution and add the wash water to the main liquid 
and distill. 

Acetone. — An appropriate aliquot of the distillate is added to a con- 
venient volume of a solution containing approximately 140 grams potas- 
sium iodide and 114 grams sodium hydroxide per liter. An excess of a 
standardized solution of sodium hypochlorite is introduced, and the con- 
tainer stoppered and shaken for at least one minute. The solution is 
then acidified with dilute hydrochloric acid, care being taken not to allow 
the mixture to become hot. An excess of a standardized solution of sodium 
thiosulphate is introduced and the excess determined by means of the 
sodium hypochlorite solution, starch solution being used as indicator. 
Six atoms of iodin convert one molecule of acetone into iodoform. 

Methyl Alcohol. — An appropriate aliquot of the distillate is freed from 
acetone by conversion into iodoform with iodin and alkali. The iodo- 
form filtered off or shaken out with petroleum ether or chloroform, the 
solvent being washed with saturated salt solution and the washings added 
to the main liquid. If preferred, a combination filtration and shake-out 
method may be used to eliminate the iodoform. The liquid is then dis- 
tilled, the distillate diluted to a definite volume and the methyl alcohol 
estimated from the refractive index as given on page 535. For approxi- 
mate results the density tables for ethyl alcohol may be used. 

Determination of Acetone by the Mercuric Iodide Method. 
Deniges. 1 — The reagent is prepared by dissolving 5 grams of mercuric 
oxide in 100 mils of water to which 20 mils of sulphuric acid have been 
added. Acetone in aqueous solution may be detected by adding 2 mils 
of this reagent to 2 mils of the solution in a test-tube and plunging the 
tube into boiling water. If no acetone is present, no precipitate will form 
within ten minutes. If the acetone is in alcoholic solution, water must 
be added prior to the addition of the reagent. Acetone may be estimated 
by taking 25 mils of the solution containing it — first diluting with water 
if the solution is an alcoholic one — adding 25 mils of the reagent, and cork- 
ing tightly in a strong flask of 90 mils capacity. The flask is set in a water- 
bath, which is raised to the boiling-point, and kept boiling for ten minutes. 
1 J. Soc. Chem. Ind., 1899, page 179. 



604 ORGANIC SUBSTANCES 

The flask is then removed from the bath, allowed to cool, and the pre- 
cipitate is collected on a weighed filter, washed with cold water, and dried. 
The weight of the precipitate multiplied by .06 (theoretically .0584) gives 
the weight of the acetone in the 25 mils of solution taken. 

Methyl alcohol and acetone can be detected in tincture of iodin by 
destroying the iodin with thiosulphate and distilling off a few mils through 
a long vertical condenser bent at about 50 cm. from the flask. Part of 
the distillate is treated according to the methods for detecting methyl 
alcohol and another portion tested for acetone. 

Determination of Acetone in Presence of Ethyl Alcohol. — A portion of 
the sample, containing about .05 gram of acetone, is placed in a 750-mil 
flask, 300 mils of freshly prepared lime-water is added, the flask is closed 
loosely with a rubber stopper, and its contents heated to 35° C; 5 mils 
of N/5 iodine solution is then added, drop by drop, and after shaking for 
five minutes, a second 5 mils is added, and so on until 40 mils in all has 
been introduced. After ten minutes, starch solution is added, the mix- 
ture cooled, acidified with 15 mils of N/1 sulphuric acid, and the excess 
of iodin titrated with N/10 thiosulphate solution. The number of mils 
of N/5 iodin solution used is multiplied by .00193 to obtain the quantity 
of acetone in the portion of the sample taken. If, during the addition 
of the iodin, the color persists after thorough agitation, more lime-water 
should be added. About .8 mil of N/5 iodin is absorbed by 1 mil of 
ethyl alcohol. When the sample contains only about 1 part of acetone 
and 100 parts of ethyl alcohol, the results are not very trustworthy, but 
in samples containing 1 part of acetone and 10 parts of ethyl alcohol the 
results are accurate and concordant. 

Acetone-resorcinol 

When a mixture of acetone and resorcinol is treated with hydrochloric 
acid gas, small prisms melting 212-213° having the composition C15H16O4 
-I-H2O are produced. The product is insoluble in water, alcohol, ether, 
and chloroform, but dissolves in alkaline solutions. It is used as an 
antiseptic. 

Benzylideneacetone, C 6 I16h = CHCOCH3 

This product, known as methyl cinnamyl ketone, methyl styrylketone, 
or acetocinnamone, forms colorless crystals melting 42° with a cumarin 
odor. It is soluble in the ordinary organic solvents. 

Salacetol, C 6 H 4 (OH)C0 2 CH 2 COCH3 

It forms fine white to faintly reddish needles, melting 71° C, soluble 
in alcohol, ether, chloroform, fixed oils, and slightly in water. It is used 
as an antiseptic and antirheumatic. 



ALDEHYDES AND KETONES 605 

Sodium Lygosinate, CO = (CH : CHC 6 H 4 ONa)27H20 

This substance is the sodium salt of dioxy-dibenzal acetone. It occurs 
in glossy, greenish prisms, soluble in cold alcohol, easily soluble in hot 
alcohol and in glycerin. Its aqueous solution has a ruby-red color and is 
alkaline in reaction. 

On ignition, 1 gram of sodium lygosinate leaves a residue of sodium 
carbonate weighing .243 gram. From the aqueous solution acids precipi- 
tate a thick yellow precipitate of diortho-cumarketone. The solution is 
fairly stable when kept in a cool place, protected from the air, and is not 
decomposed on boiling, but is decomposed by weak acids, even the car- 
bonic acid of the air. Its powder produces sneezing. It is used as an 
antiseptic and bactericide in gonorrhoea and similar ailments. 

Methyl heptenone, CH 3 C(CH 3 ) =CHCH 2 CH 2 COCH 3 

Methyl heptenone is an unsaturated ketone found in certain oils such 
as linalce, citronella, and lemon-grass. It is a colorless, mobile, inactive 
liquid with an amyl acetate-like odor. It boils 170-174°, readily forms 
a bisulphite compound and a semicarbazone melting 136-138°. 

AROMATIC KETONES 

The only aromatic ketones of importance in medicine are acetophenone 
camphor and thujone, though carvone and fenchone will sometimes occur 
as the flavoring principles in some elixirs and cough remedies. 

The ketones have the general formula R — CO — R', where R and R' 
represent different or identical radicles, one of which must of course be 
aromatic. 

Acetophenone, C 6 H 5 COCH3 

Acetophenone or phenyl methyl ketone is known in medicine under 
the name of Hypnone, and is employed as an hypnotic for insomnia. 

It occurs in laminary crystals, melting 14° C, so that it will often be 
encountered as a liquid, and boiling at 202°. It has a pungent taste and 
an odor recalling that of orange blossoms. It is soluble in alcohol, ether, 
chloroform, fatty oils, and to a slight extent in water. 

On reduction it yields phenyl methyl carbinol, C6H4CH(OH)CH3, and 
on oxidation it is resolved into benzoic acid and carbon dioxide. It reacts 
with hydroxylamine to form an oxime, and with phenyl hydrazine to give 
an hydrazone. 

Its low melting-point, odor and ketone-like properties are sufficient 
for its identification. 



606 ORGANIC SUBSTANCES 

Benzophenone, C 6 HoCOC 6 H 6 
This body forms crystals melting 48-49°. 

Trioxybenzophenone, C 6 H40HCOC 6 H 3 (OH)3 

Trioxy benzophenone or salicylresorcinol ketone, is obtained by the 
interaction of salicylic acid and resorcinol. It melts 133° C. and is slightly 
soluble in water, but dissolves in hot alcohol and benzol. It is used as 
n antiseptic, antipyretic, and analgesic. 

Oxyphenylbenzylketone C 6 H 5 CH(OH) COC 6 H 5 

This ketone, which is known as Benzoiin and bitter almond oil cam- 
phor, is a reaction product of benzaldehyde, potassium cyanide, and. ethyl 
alcohol. It forms colorless crystals, melting 135-137°, soluble in alcohol 
and hot water. 

It has antiseptic properties and is sometimes used in ointments for 
ulcers and varicose veins. 

Lowry in the new edition of Allen divides the cyclic ketones into four 
groups. 

a. CioHigO group, with a single ring: type menthone. 

b. CioHi 6 group, with a ring and a double bond or two double bonds: 
type camphor. 

c. C10H14O group, with a ring and two double bonds, two rings and 
one double bond, or three rings. 

d. Ketones with more or less than 10 carbon atoms such as matico- 
camphor. 

Carvone, C 10 Hi 4 O 

CH3 CH2 

v 



i, 



H 2 C CH 2 
HC C=0 

V 

I 

CHO 

This ketone occurs in the d-form in caraway and dill oils and in the 
Worm in spearmint oil. None of these oils are of special interest to the 



ALDEHYDES AND KETONES 607 

drug chemist. At the present time by far the greater amount of spear- 
mint oil is used in this country as a flavoring agent for chewing gum. 

Carvone is a colorless liquid with a strong odor suggestive of caraway. 
The d-form boils 224° C., specific gravity .9598 at 20° (a)n = +62.07°, 
the Z-form has practically the same constants with a minus rotation. 

It does not add bisulphite, but yields a well crystallized oxime, melt- 
ing 72°, inactive form 93°. Its phenylhydrazone melts 109-110° and its 
semicarbazide 54-56°. It also forms a crystalline compound with hydro- 
gen sulphide when an ammoniacal alcoholic solution is treated with this 
gas. 

For the determination of carvone in oil of spearmint the following 
methods appear to give satisfactory results : 

Walther Method. — Two to 5 grams of carvone or the carvone-bearing 
oil are placed in a wide-neck flask and 10 grams of a freshly prepared 
aqueous solution (2:3), of hydroxylamine hydrochloride added. 

Then add 25 mils aldehyde free absolute alcohol and 2 grains bicar- 
bonate sodium, connect the flask with a return-flow condenser, and heat 
to gentle boiling on a water-bath. 

After cooling to 25°, add 6 mils HC1 (1.12), and transfer to a 500-mil 
volumetric flask, rinsing out the condenser and flask with dilute HC1, 
followed with water. Filter, and in 25-50 mils of the filtrate titrate the 
excess of hydroxylamine. 

The titration of the hydroxylamine is carried out as follows: 

Methyl orange is added (about 1 drop), and the mineral acid neutral- 
ized with alkali. Then phenolphthalein is added and the hydroxylamine 
titrated with N/10 NaOH. 

The difference between the titration corresponding to the weight of 
hydroxylamine taken and that corresponding to the hydroxylamine left 
represents the amount converted into carvoxime. 

Each mil of N/10 NaOH is equivalent to .015 gram carvone. 

Nelson 1 finds this method satisfactory for determining pulegone, 
thujone, menthone, and camphor, but not fenchone. 

H. Labbe Method. — This method rests on the fact that carvone is dis- 
solved easily in a boiling solution of sodium bisulphite with the formation 
of a dihydro-di-sulphonate, of which the constitution has been established. 

First Method of Determination. — Five grams of the oil are placed in a 
little flask, fitted with a ground-in condenser, and about 15 grams of sodium 
bisulphite dissolved in water with Na2C03 are added. To render the 
boiling regular, a few pieces of porcelain are put in the flask. After 1| 
hours boiling, allow to cool thoroughly, and take up the residual oil with 
ether, washing out condenser and flask with the same solvent, and sepa- 
rate the aqueous layer in a small separatory funnel. 
1 J. Ind. Eng Chem., 1911, 3, 588. 



608 ORGANIC SUBSTANCES 

The ether solution is dried carefully with anhydrous sodium sulphate, 
filtered into a small weighed flask, the major portion of the ether evaporated 
in a partial vacuum, and the last traces by gentle heating. The increase 
in weight gives the hydrocarbons, or constituents not carvone. 

Second Method of Determination. — Since carvone on simply heating 
with a solution of sodium bi-sulphite and sodium carbonate furnishes a 
dihydro-di-sulphonate derivative which is very soluble, one is able, by 
using a titrated solution of bisulphite, to calculate from the dimunition 
in strength in SO3 after boiling, the proportion of carvone. 

To titrate the solution of bisulphite before and after, a centinormal 
solution of iodin in potassium iodide is used, which, as has been demon- 
strated has no action on the dissolved carvone derivative. 

One gram to 1J grams of carvone and 10 mils of a saturated NaHSOs 
solution containing .2-3 gram NaHSOs per mil are used for the estimation. 

The heating is effected as in the first method except that the upper 
end of the condenser is fitted with a U-tube trap filled with a freshly alka- 
line solution to restrain any liberated SO2. 

After cooling, the SO2 is titrated in a suitably diluted aliquot. 

By this method, an absolutely pure carvone showed 100.3 per cent 
and a 97 per cent commercial carvone 96.9 per cent. 

The titration of the NaHSOs is expressed in SO2, and the SO2 con- 
sumed by the carvone, shown by the difference in titration, goes to form 
Ci Hi4O(SOsNaH) 2 . Therefore two molecules of SO2 consumed corre- 
spond to one molecule of carvone present. 

Camphor, Ci Hi 6 O 

The dextro camphor, Formosa or Japan camphor, is the official or 
gum camphor and occurs in the camphor laurel, Cinnamonum camphora 
(Lauracese), a large tree growing in southern China, Japan, and several 
adjacent islands. The camphor is found dissolved in a volatile oil, found 
most abundantly in the roots, but is generally distributed throughout 
the entire tree. d-Camphor also occurs in small quantities in a number 
of essential oils such as sassafras leaves, cinnamon root, spike, rosemary, 
sage, etc. The l-iorm occurs in the oils of feverfew and tansy. 

Artificial camphor is now prepared to a considerable extent and is 
a commercial article. When properly prepared and purified it can be 
distinguished from the natural only by having no optical rotation. By 
mixing equal parts of d- and ^-camphors obtained from natural sources, 
a racemic camphor is obtained which is identical in every respect with 
the synthetic. 

In making camphor artificially one of the products obtained is pinene 
hydrochloride. This substance forms a white crystalline mass which 



ALDEHYDES AND KETONES 609 

closely resembles camphor, and has been sold as artificial camphor or 
turpentine camphor. It is soluble in alcohol but not in water, melts 
125° and boils about 208°. It is used as an antiseptic both externally 
and internally, and among its other uses is recommended for checking the 
flow of perspiration. The presence of the halogen is readily detected by 
heating it on a copper wire and noting the green color produced. 

The structural formula of camphor is as follows, and it forms three 
classes of derivatives, a, (3 and t, the particular portion of the nucleus 
effected being indicated. 

CH 2 — CH CH 2 <-« 

I 

C(CH 3 ) 2 <-7r 

I 

0->CH 2 — C CO 

CH3 

Camphor is considered valuable for a number of different disorders 
and plays an extensive role in medicine. It is a stimulant and sedative 
according to the dose, also antispasmodic, anaphrodisiac, expectorant, 
carminative, and diaphoretic. Possessing as it does all these properties, 
it is combined with a number of other drugs which are dispensed in the 
form of pills and tablets. 

The best known preparations containing camphor are of course the 
official spirit containing 10 per cent of the substance in alcohol, camphor 
liniment or camphorated oil containing 20 per cent of camphor in olive 
or cottonseed oils; soap liniment or liquid opodeldoc containing 4-5 per 
cent camphor; camphorated tincture of opium or paregoric, camphor 
cerate, and camphor water. 

Camphor is an ingredient of Warburg Tincture and of inhalants both 
of oil and glycerin. 

The common combinations used in pills or tablets include coryza for- 
mulas where the camphor functionates with quinin, morphin, atropin, and 
ammonium chloride, sometimes with aconite; Sun cholera mixture, con- 
sisting of camphor, opium, rhubarb, Capsicum, and peppermint; rhinitis 
mixture of camphor, quinin, and belladonna; and brown mixture of cam- 
phor, licorice, opium, benzoic acid, ammonium chloride, tartar emetic, 
and anise. Other mixtures include those of camphor with opium and 
Hyoscyamus; with opium and tannic acid; with valerian and Hyoscyamus; 
with morphin, ipecac, and potassium nitrate; with Podophyllum and 
ipecac; with salol, opium, bismuth subnitrate, and peppermint, etc. 

Camphor is often dispensed in ointments intended to allay congestion, 
rheumatism, and sprains. It will be found with menthol and boric acid; 
quinin, turpentine, phenol, and opium; with mustard oil and aromatic 
balsams, etc. 



610 ORGANIC SUBSTANCES 

As ordinarily encountered camphor occurs in blocks or masses which 
are white and translucent, or in small crystals called " flowers of camphor." 
The odor is characteristic and the taste pungent and aromatic. Camphor 
melts at 175° C, boils 204° C, and is inflammable, burning with a luminous 
smoky flame, (a) #=±44.22° in 20 per cent alcoholic solution. It is 
very sparingly soluble in water, but goes into solution in all the organic 
solvents, and in fixed and volatile oils. When triturated with menthol, 
thymol, phenol, or chloral hydrate liquefaction takes place. When thrown 
on the surface of clean water it goes through a rapid whirling motion 
which is arrested by the addition of a very small quantity of oil. 

On exposure to the air it is slowly volatile, and when moderately 
heated sublimes without leaving a residue. 

Camphor does not combine with bisulphites, but it does form a well- 
defined oxime melting 118-119°, and a semicarbazone melting 236-238°. 
To prepare camphor oxime a gram or its proportional amount of the sub- 
stance is dissolved in 15 mils alcohol, treated with an equivalent amount 
of an aqueous solution of hydroxylamine hydrochloride 1-1 and 1.5 grams 
sodium hydroxide, and warmed under a reflux for an hour or two. It 
is well to allow the mixture to stand for about twelve hours after this 
treatment, and on adding considerable water and enough acetic acid 
to neutralize the alkali, the oxime will be precipitated. It can be crys- 
tallized out of hot dilute alcohol. 

The semicarbazone of camphor may be prepared by dissolving one 
gram of semicarbazide hydrochloride and 1.23 grams sodium acetate 
anhydrous in the smallest amount of water possible, and adding the mix- 
ture to one gram of camphor in absolute alcohol. After warming the solu- 
tion, it is stoppered and allowed to stand overnight, and the semicarba- 
zone is then precipitated by water and recrystallized from alcohol. 

Upon reduction camphor is converted into borneol, and on oxidation 
to camphoric acid and further to tribasic camphoronic acid. 

Camphor will absorb gaseous hydrogen chloride, nitrogen peroxide, 
and sulphur dioxide, forming liquids from which the gases are liberated 
on the addition of water. The sulphur dioxide compound is used as a 
disinfectant. 

The odor of camphor is generally a sufficient indication of its presence 
in a medicinal preparation. There will seldom if ever be any instances 
where other things will mask the camphor odor, though camphor may 
often mask the odor of other ingredients, especially menthol. 

The only substances which might be confused with camphor from the 
point of view of odor are pinene hydrochloride, monobromated camphor, 
and chloretone. 

If it is necessary to go further with the identity, the camphor can be 
conveniently converted to the oxime and its melting-point determined. 



ALDEHYDES AND KETONES 611 

The oxime has a peculiar odor suggestive of camphor, but more intense 
and less pleasing. 

Much work has been done on the estimation of camphor and very 
little of it is of any value to the drug analyst. 

The extensive use of camphor in medicine and the fact that the Pharma- 
copoeia includes preparations which must contain definite quantities of 
camphor make it imperative that there should be a reliable method of 
assay. There have been in vogue for some time procedures depending on 
the rotation of an alcoholic, benzol, or oil solution and on the loss by 
evaporation, but they are open to objection, and in certain instances the 
results might easily be misinterpreted. Artificial camphor is without rota- 
tory power, natural camphor might contain a portion of the lsevo body, 
the rotation varies with the strength of the solvent, and fixed oils them- 
selves on heating often undergo loss or gain in weight. These are a few 
of the reasons which call for a method based on a more substantial foun- 
dation. 

Camphor, being of ketonic character, f onns with hydroxylamine a well 
defined oxime, C10H16NOH, and advantage has been taken of this property 
in assaying camphor preparations, the procedure being based on Walther's 1 
carvone estimation. The procedure is simple and may be applied directly 
to spirit of camphor. Of the sample 25 mils are measured into an Erlen- 
meyer flask of 100 mils capacity, 2 grams of sodium bicarbonate are added, 
and then, accurately, from a burette, 35 mils of a hydroxylamin solu- 
tion (20 grams NH 2 OH-HC1+30 mils H 2 0-}-135 mils absolute alcohol 
aldehyde free). The flask is connected with a reflux condenser, and 
heated to gentle boiling for two hours; it is then cooled to 25° C, treated 
with a mixture of 6 mils hydrochloric acid (1.12 specific gravity +6 mils 
water) transferred to a 500-mil volumetric flask, rinsing out the condenser 
and flask with water, and finally made up to volume; 50-mil portions are 
filtered off and titrated as follows : Methyl orange is added and the mineral 
acid neutralized with normal alkali, then phenolphthalein is added and 
the hydroxylamine hydrochloride titrated with N/10 alkali. A blank 
must be run, using the same amount of hydroxylamine solution and 
25 mils of alcohol to correspond with the spirits of camphor, the difference 
in titrations representing the hydroxylamine converted into camphor oxime. 
Each mil of tenth-normal sodium hydroxide is equivalent to .01509 gram 
of camphor. 

The writer has sometimes obtained good results with this method and 
again has obtained figures which were difficult to explain. The same 
report comes from other workers. It may be stated, however, that with 
a pure camphor carefully freed from water and all impurities it is possible 
to get results which render the method available in analytical work. It 
1 Pharm. Centralhalle, 1900, 41 : 613. 



612 ORGANIC SUBSTANCES 

is probable that in case where peculiar results were obtained the fault was 
due to the grade of camphor employed, or to the personal equation of the 
worker. 



Oxaphor 
Oxaphor is a 50 per cent solution of oxy camphor. 



C 8 H 



CHOH 
/ 

= CioHi602, 



8-Q-14 



CO 

a derivative of camphor in which a hydrogen atom has been replaced by 
a hydroxy 1 group. 

It is a white crystalline powder, neutral in reaction, melting at 203 
to 205° C. It is soluble in about 50 parts of cold water, more soluble in 
warm water, and readily soluble in all organic solvents except petroleum 
benzin, in which it is soluble, but from which it crystallizes in feathery 
aggregations. On prolonged keeping it is prone to undergo decompo- 
sition, but it keeps permanently in alcoholic solution. It volatilizes gradu- 
ally at ordinary temperature and readily with steam. 

Oxycamphor, being decomposed on prolonged exposure to the air, 
is marketed only in the form of the 50 per cent alcoholic solution under 
the name of " oxaphor." 

It is used as a substitute for morphin in respiratory disorders. 



Camphoric Acid 

When camphor is treated with nitric acid 1.37 specific gravity, it is 
converted to camphoric acid, Ci Hi 6 O4, and on further boiling camphor- 
onic acid, C9H14O6, results with a very small quantity of isocamphoronic 
acid. 

Camphoric acid is dibasic and has the accompanying formula 



ch 2 — ch— cook 

I 

C(CH 3 ) 2 

CH 2 — C COOH 

I 
CH 3 



ALDEHYDES AND KETONES 613 

while camphoronic is tribasic 

COOHCOOH 

I 
C(CH 3 ) 2 

i 
CH 2 — C— COOH 

CH3 

a stronger chain compound and isocamphoronic is 

CH 2 : — CH CH2 

I I' 

C(CH 3 ) 2 COOH 

I 
COOHCOOH 

Camphoric acid is odorless, melts 186°, and at a higher temperature 
is converted to the anhydride. It is somewhat soluble in water, readily 
in the organic solvents and oils. It is dextrorotatory (a)z>H-46 , but a 
lsevo form can be obtained from ^-camphor and the combination of the two 
produces the racemic acid, melting 204°. When heated alone or boiled 
with acetic anhydride, it yields the anhydride which crystallizes from 
alcohol, melting 217°. 

Camphoric acid is an astringent and antiseptic and is used externally 
in skin diseases, as a gargle alone or mixed with other substances, and 
for diarrhea, pneumonia, pulmonary affections, calculi, and diseases of 
the urinary tract. 

There are many derivatives of this acid which have been offered as 
possessing certain medicinal properties not obtainable with the parent 
substance. 

Phenyl hydrogen camphorate, melting 100° 

Thymyl hydrogen camphorate, melting 89° 

Guiacyl hydrogen camphorate, melting 112° 

Diguiacyl camphorate, melting 124° 

Eugenyl hydrogen camphorate, melting 115-116° 

Naphthyl hydrogen camphorate, melting 121-122° 

Monobromated Camphor, Ci Hi 5 BrO 

This substance is an a-derivative and is a-Bromocamphor 

CHBr 

A 

CsHi4 

\l 

C ■> CO 

ft) 



c i* * r % °S~ 



614 ORGANIC SUBSTANCES 

It forms colorless, prismatic needles or scales, having a mild camphor- 
aceous odor. It melts 76°, boils 274° without decomposition, sublimes 
readily and is volatile with steam. It is insoluble in water but dissolves 
in the organic solvents and oils and in concentrated sulphuric acid from 
which it separates unchanged on adding water. It is dextrorotatory 
(a)i>+139 in saturated alcoholic solution. 

It is decomposed on boiling with silver nitrate solution. On reduction 
with sodium amalgam in alcoholic solution it yields camphor. 

Monobromated camphor will often be found mixed with acetanilid 
and caffeine, and sometimes with the addition of salicylates, Hyoscyamus 
and Gelsemium. 

Estimation of Monobromated Camphor in Tablets. — W. O. Emery. — 
Ascertain the weight of twenty or more tablets, reduce to a fine powder, 
and keep in a small tube or specimen bottle provided with a tightly fitting 
cork or glass stopper. Weigh out on a metal or glass scoop an amount 
of the sample equivalent to not less than 100 nor more than 200 mg. of 
the camphor derivative alleged to be present. Transfer quantitatively 
to a small (100 mil) round-bottomed flask, with 20 mils of 96 per cent 
alcohol and 10 mils of water, containing 15 grams of 1 per cent sodium 
amalgam. Connect flask by means of a rubber stopper with a short 
vertical reflux, perferably of the Allin or of the worm type. Heat the 
mixture over a wire gauze just sufficient to cause the liquid to boil gently 
for a period of not less than thirty minutes. After cooling slightly, wash 
out the condenser tube, first with 5 mils of alcohol, then 5 mils of water, 
receiving the washings in the flask below. Remove latter .to the steam- 
bath, heating thereon another hour, or until the evolution of hydrogen 
has nearly or quite ceased. Toward the latter part of this operation, 
render the liquid about neutral with a few drops of acetic acid in order 
to further reduction. Transfer the contents of flask to a separatory funnel 
preferably of the Squibb type, withdrawing and washing the mercury in 
a second separatory funnel with at least two 50-mil portions of water. Pass 
the several aqueous solutions quantitatively through a small filter, collect- 
ing the clear filtrate in a suitable beaker. Precipitate with silver nitrate 
after the addition of about 5 mils of nitric acid, and proceed with the 
determination of the resulting silver bromide in the usual gravimetric way, 
employing if available a Gooch crucible in the operation of filtering The 
weight of the silver bromide multiplied by the factor 1.23 will give the 
quantity of monobromated camphor originally present in the sample taken 
for analysis. A control on the amalgam should be run in order to deter- 
mine whether any correction is necessary with respect to the presence of 
halogen in material quantity. 

This procedure can be used when monobromated camphor occurs alone 
or in combination with caffein and antipyretics. 



ALDEHYDES AND KETONES 615 



Fenchone, Ci Hi 6 O 

Fenchone bears a close resemblance to camphor in odor and general 
properties, but it is a liquid. The d-form occurs in fennel and the Z-form 
in thuja oils. It melts" 5-6°, specific gravity .943-.946, forms an oxime 
melting 164-165°, but does not react with bisulphite or phenylhydrazine. 

Thujone, Ci Hi 6 O 

Thujone or tanacetone is a constituent of the oils of thuja, tansy, sage, 
wormwood, and other species of Artemisia. It has a characteristic odor 
to which the oils owe in part their aroma, which odor serves a ready 
means for its identification. 

Pure thujone is a colorless, oily liquid, boiling 84.5° at 13 mm., specific 
gravity .9126 to .916 at 20°, and rotation +68°. It forms a bisulphite 
compound, an oxime melting 54-55°, and a semicarbazone melting 171— 
172°. 

As thujone is a normal constituent of oil of wormwood its presence 
would naturally be expected in the beverage known as absinthe, but in 
neither of the white nor green varieties, as sold in this country previous 
to the embargo, was the writer able to detect the slightest trace. 

Tansy oil is used in female pills, and wormwood oil is an ingredient of 
a certain type of antiseptic liniment combining the virtues of a number 
of essential oils in menstruum of acetone or alcohol. 

Thuja oil, from Thuja occidentalis, the Arbor Vitse or White cedar, 
is used as a tonic and emmenagogue, and as an antiseptic in skin diseases. 

Pulegone 
CK 3 CHa 

v 

t! 
c 

/ \ 

H 2 C CO 

I I 

H2C CH2 

!H— CH3 



^ 



Pulegone is the chief constituent of the oil of Mentha pulegium, Euro- 
pean pennyroyal, and occurs also to a considerable extent in the oil of 
Hedeoma pulegioides. These oils, though from botanically different 
species, are similar in composition and are probably used indiscriminately 
as " pennyroyal oil " in medicinal products. 



616 ORGANIC SUBSTANCES 

Pulegone is a colorless liquid with a sweet peppermint-like odor, boiling 
130-131° at 60 mm., specific gravity .9323 at 20° C, rotation +22.89°. 
Its oxime melts 118-119°, and its semicarbazone at 170°. It forms a 
bisulphite compound. When heated with water to 250° under pressure, 
it yields acetone and methyl hexanone, and on oxidation with potassium 
permanganate acetone and beta-methyl adipinic acid. 

Menthone, Ci Hi 8 O 

Z-menthone occurs in peppermint oil. It is a colorless liquid with a 
menthol-like odor, boiling 207°, specific gravity .8960 at 20°, rotation 
-28.18°, oxime melting 59° and semicarbazone melting 184°. It does 
not unite with bisulphite. 

THE CARBOHYDRATES 

The carbohydrates are properly considered at this point, as they 
possess either the properties of ketone alcohols or aldehyde alcohols. 
They embrace the very important group of substances known as the sugars 
which are much more interesting to the food than to the drug chemist. 
The latter, however, will often meet with sugars, as they make up the 
bulk of some of the most important classes of galencial preparations, 
including pills, tablets, elixirs, syrups, and powders, and their determi- 
nation will often be necessary in arriving at the ultimate composition of 
a sample under investigation. 

Cane sugar or sucrose is of common occurrence in all of the above- 
mentioned classes; commercial glucose which is made up in large part of 
dextrin and maltose, is used as a builder in pill masses; milk sugar or 
lactose is present in tablet triturates and in powders as a diluent; maltose 
will be found in malt extracts; and a mixture of several different carbo- 
hydrates is usually found in the many different infant foods. 

The carbohydrates with aldehyde or ketone groups form osazones 
with phenylhydrazine, and these bodies are of value in arriving at the 
identity of a sugar. It is inadvisable, however, to place too great a depend- 
ence on these compounds, because the melting-points are in some instances 
fairly close to each other, and it is often a question whether one is dealing 
with an impure osazone of an individual, or the mixed osazones of two 
different sugars. 

For a detailed account of the chemistry of the carbohydrates one 
should refer to the special books on the subject; but as a guide to the 
workers the accompanying table has been compiled, and in it will be found 
a brief summary of the principal distinguishing properties of these sub- 
stances. 



ALDEHYDES AND KETONES 



617 





Common Name 


Formula 


Products of 
Hydrolysis 


Specific 
Rotation 


Osazone 


Dextrose ...... 


Grape Sugar or 
Glucose 


CH>OH(CHOH) 4 
CHO 




+52.80 


Melts 204-5° 


Levulose 


Fruit sugar or 
Fructose 


CH 2 OH(CHOH) 3 
COCH 2 OH 




—90.2° 


Melts 204° 


Sorbose 




CeHisOs 




—42° 


Melts 164° 


Galactose 




CH 2 OH(CHOH) 4 
CHO 




+81° 


Melts 196 


Arabinose 








+105° 


Melts 160° 


Sucrose 


Cane sugar or 
Saccharose 


Cr^H^Ou 


Dextrose and 

levulose 


+66.50 


Xon-reducing 


Trehalose 


Occurs in Manna 




Dextrose 


+197° 


Xon-reducing 


Lactose 


Milk sugar 


Cr.H-Oii 


Dextrose and 

Galactose 


+52.50 




Maltose 




C, 2 H-Oii 


2 molecules of 
Dextrose 


+ 138° 




Starch 




(CoHioOo)?! 


Acid hydrolysis 
gives Dextrin 
















and then dex- 












trose 












Diastase gives 












Dextrin and 












Maltose 






Dextrin 




(CYELoOo),, 








Cellulose 




(C6HloOo)fl 












CosHesOai 


Levulose 


—39.5 









The accompanying method for detecting the nature of the carbohy- 
drates present in mixtures is included. 

Identification of Carbohydrates. — (A) To 5 mils of a weak solution 
of the substance add a few drops of 15 per cent alcohol solution of a-naph- 
thol; float this over cone, sulphuric acid, a violet or blue zone at the line 
of contact indicates a carbohydrate. 

If the substance is insoluble in water dissolve in 25 per cent sulphuric 
acid and float over this solution a mixture of water and a-naphthol and 
observe as above. 

(B) Shake one gram of the substance with 10 mils water. Decant 
or filter from any insoluble residue which may be Starch or Cellulose. 
Save nitrate. 

To insoluble matter in (^not on filter paper) add few drops dilute aqueous 
solution of iodin, blue color shows starch. 

Filtrate divide into 3 portions a, /3, and y. 

a. Divide into 2 portions 1 and 2. To 1 add an equal volume of 94 per 
cent alcohol; a precipitate indicates Dextrin. To 2 on a white slab add 
a few drops of dilute solution of iodin; blue color indicates cooked starch; 
reddish-brown indicates Dextrin. 

0. Boil with Burford's solution of copper acetate; precipitate of 
CU2O indicates either Dextrose or Levulose or both. Filter and treat 



618 ORGANIC SUBSTANCES 

filtrate as follows: Add excess of basic lead acetate solution; filter and 
to filtrate, add sodium sulphate solution in excess and filter from lead 
sulphate. To filtrate, which must still be blue (if not add a few drops of 
copper sulphate solution) add sodium hydroxide to make alkaline and 
heat to boiling; a red precipitate of CU2O indicates Maltose or Lactose 
or both. Filter. To filtrate add a few drops sulphuric acid and boil, 
neutralize with excess sodium hydroxide, add a few drops copper sulphate 
and heat to boiling; a red precipitate of CU2O indicates Saccharose (Cane 
Sugar) . 

7. To determine whether Maltose or Lactose are present. Add 
ammonia in excess, add a few drops of alkaline bismuth solution and set 
the tube in water at a temperature of about 60° C. Maltose solution 
reduces the bismuth, while Lactose does not at this temperature within 
one-half hour. 

To detect Lactose. To about 5 mils of strong nitric acid; add .5 gram 
original substance and warm gently until red fumes begin to come off. Set 
tube in about 200 mils hot water and allow it to remain there until cold ; in 
a few hours white crystalline mucic acid separates if lactose is present. 

Hediosit 

Hediosit, C7H12O7, is the lactone or inner anhydride, of alpha-gluco- 
heptonic acid, CH 2 OH • (CHOH) 5 COOH. 

It is a white, crystalline, odorless powder, with a sweet taste. It is 
readily soluble in water, slightly soluble in alcohol, and almost insoluble 
in ether. The aqueous solution is acid toward litmus and does not reduce 
in Fehling's solution. 

If 1 gram of hediosit is heated on a boiling-water bath with 1 mil 
of water and .5 gram of phenylhydrazine, and a few mils of absolute 
alcohol added, a fight-colored crystalline mass will form, which after 
recrystallization from dilute alcohol melts at 172° C. 

If 1 gram to 2 grams of hediosit weighed into a flask are dissolved in 
10 to 20 mils of water by warming and a few drops of phenolphthalein 
solution added, 9.1 to 9.6 mils of half -normal sodium hydroxide per gram 
of hediosit taken should be required to neutralize the solution. 

If 9 grams of hediosit is dissolved in water to make 100 mils and allowed 
to stand at the ordinary temperature for twenty-four hours the solution, 
when polarized at 17° C, should show a specific rotation of about -52° 
for the sodium fine. After neutralization with caustic soda the solution 
has a slight dextrorotation. 

Hediosit is used as a sweetener of the food of diabetic patients. 



ALDEHYDES AND KETONES 619 



ANALYSIS OF INFANT FOODS 

These products consist usually of carbohydrates and milk solids in 
varying proportions. They often contain sucrose and sometimes dextrose, 
but the carbohydrates, which are present in almost all cases are dextrin, 
maltose, and lactose. 

As sold on the market these foods are usually in the form of dry 
powders, and the analysis in so far as the determination of the content of 
nitrogen, ash, fat, and moisture are concerned, is the same as for any food 
product. For fat, the Rose-Gottlieb method is preferable to any other. 

Assay for Carbohydrates. — The method of estimating the individual 
carbohydrates in infant foods was worked out in my laboratory by Mr. 
T. M. Rector during the course of an extended research which we made 
on these products. 

In preparations containing mixtures of sucrose, maltose, lactose, and 
dextrin, the sucrose is determined by loss of rotation after inversion with 
invertase. The dextrin is determined by loss of polarization after pre- 
cipitation with lead acetate and ammonia. The combined polarization 
of the sucrose and dextrin is subtracted from the total polarization, giving 
the polarization of the maltose and lactose. A copper reduction is then 
run on an aliquot of the solution and the amount of copper reduced by 
1 gram of the sample is calculated. From this value and the combined 
polarization of the maltose and lactose the percentages of these sugars 
are calculated by a formula. 

No claims are made for the availability of this method beyond mix- 
ture of carbohydrates of the malted milk type or those prepared syn- 
thetically from the same ingredients. Furthermore, the conversion of 
starch to maltose and dextrin in the preparation of these foods is probably 
incomplete, and the mixture unquestionably contains dextrin-like sub- 
stances in various stages of conversion. For this reason the results 
obtained for dextrin must of necessity be only approximate, and while 
with known mixtures of the pure ingredients the determination yields 
theoretical results, in commercial articles the figures obtained would 
require slight modifications to obtain these actual values. 

The specific rotary power of maltose is 138, while the same value. for 
lactose is only 52.5. On the other hand, lactose has a greater reducing 
power on Fehling's solution than its isomer. Either of these values would 
serve as a basis to determine the sugars if the total sugar was known, but 
in the absence of that data a formula, based in the ratios between the 
polarization and copper-reducing power of the sugars, was devised to 
determine the ratio of the quantity of one sugar to the other. Then, 
from the polarization due to the two sugars, their percentages in the mix- 
ture was calculated. 



620 



ORGANIC SUBSTANCES 



To get the best result the constants of the difference carbohydrates 
should be determined by the analyst himself in order to obviate personal 
errors as well as possible errors in his polariscope. The constants used 
are set forth in the following table : 



Carbohydrates 


Polarization (Ventzke) 


Cu.O per gram 


Maltose 

Lactose 


207.5 

79 

79.2 
100 
300 


1.277 

1.556 

2.232 






Dextrose 


Sucrose 


*Dextrin 





* The value used for dextrin was the figure given in the text books. Of several commercial samples 
of declared purity, none ran over 250°. 

The copper-reduction figures were arrived at by using a quantity of 
sugar that would give about 225 mg. of CU2O in a reducing sugar deter- 
mination conducted according to the method of Munson and Walker. The 
analytical procedure follows: 

Weigh out 32.5 grams -of the sample and transfer dry to a 250-mil. 
graduated flask by means of a wide-stemmed funnel. Add 150 mils of 
water and digest for at least two hours, shaking frequently. Then add 
10 mils each basic lead acetate and alumina cream, shaking flask after 
each addition, and make up to the mark with water. Filter into a flask 
through a ribbed filter, keeping the funnel covered with a watch-glass. 
Add sufficient crystals of normal potassium oxalate to remove excess of 
lead, allow precipitate to settle and filter through a dry double filter, being 
sure to guard against loss by evaporation. Preserve 25-50 mils of this 
solution overnight, to destroy birotation, and polarize in a 200-mm. tube. 
Multiply reading by 2 and denote product by a. 

Transfer 50 mils of the solution to a 100-mil volumetric flask, add 
invertase and keep at from 25-30° C. overnight, in an incubator if neces- 
sary. Add 5 mils alumina cream, make up to mark, mix, filter, and polar- 
ize in a 200-mm. tube. Multiply reading by 4 and denote product by b. 

To another aliquot of the original solution of 50 mils contained in a 
100-mil volumetric flask, add 25 mils of a 10 per cent solution of lead 
acetate and 10 mils of strong ammonia. Make up to volume, shake and 
allow precipitate to settle. Filter through a ribbed filter with the proper 
precaution to prevent evaporation, and polarize solution immediately 
in a 200-mm. tube. Multiply reading by 4 and denote product by c. 

Make up 25 mils of the original solution to 250 mils and run a copper 
reduction on 25 mils of this solution according to the method of Munson 
and Walker. Divide the weight of the reduced CU2O by .325, the amount 
of sample represented by the aliquot taken, and denote quotient by d. 



ALDEHYDES AND KETONES 621 

In most malted milks and similar products this amount will reduce between 
200 and 250 mg. of CU2O. If the weight is outside these limits, the amount 
of solution should be adjusted to bring the value within their bounds. 

CALCULATIONS OF CARBOHYDRATES 
Dextrin 



P=the polarization of 26 grams pure dextrin in 200 mm. tube at 
20°C. = 300. 



Then o = per cent dextrin in sample. 



Sucrose 
Sucrose is calculated from Clerget's formula, which in this case is: 
100 (a -b) 



142.66 -~ 



= per cent of sucrose in sample = s 



Maltose and Lactose 



P= polarization of 26 grams of pure maltrose in 200-mm. tube at 
20° G. = 207.5. 

P f = polarization of 26 grams of pure lactose under these same con- 
ditions =79. 

R = grams of CU2O reduced by 1 gram of maltose under conditions 
of method. 

R f = grams of CU2O reduced by 1 gram of lactose under same con- 
ditions. 

x — parts of maltose in 100 parts of reducing sugar. 
100 —x = parts of lactose in 100 parts of reducing sugar. 

7 7 =per cent of total reducing sugar. 

*S = per cent of sucrose in sample. 

ml _ c-s Px+(100 -x) P' 

inen 









d £x+(100 - 


x)R' 








100 (c -s) 


= T 




Px+P'(10Q-x) 




Tx = 


= per 


cent maltose. 




r(ioo 


-x)- 


= per 


cent lactose. 





If sucrose is absent, this formula is simplified, the first number becom- 
ing c/d. By its use any two dextrorotary sugars may be determined, 
without knowing the total sugars, by substituting the prooer values for 
their polarization and copper reduction. 



622 



ORGANIC SUBSTANCES 



In the appended table the analyses of some commercial brands of 
infants foods are shown. A and B are samples of malted milks put out 
by different firms. The others would be recognized as much advertised 
infant foods if their names were given. 



Sample 


a 


b 


c 


d 


Dextrin 


Maltose 


Lactose 


Sucrose 


Dextrose 












Per Cent 


Per Cent 


Per Cent 




Per Cent 


A 


126.4 




89.6 


.691 


12.3 


38.3 


12.1 






B 


126.4 




88. 


.694 


12.8 


37.1 


14.1 






C 


87.4 


58.4 


54 


.322 


11.1 


11.1 


11.6 


21.86 




D 


149 




117.8 


.786 


10.4 


55.5 






2.5 


E 


43.2 




28.4 


.739 


4.9 


4.2 






29.5 



Samples A, B, and C contain considerable milk solids, having from 
6 to 10 per cent of butter fat besides the milk sugar and casein. Sample 
C appeared to be a malted milk with cane sugar added. Sample E con- 
tained a large amount of unconverted starch besides the soluble carbo- 
hydrates. 

With the exception of sample E, none of these products gave a blue 
reaction with iodin. It is probable that the starch was converted entirely 
to dextrins, and that the dextrins present has a Ventzke value nearer 250 
than 300. If this were so, the dextrin value would range higher in the 
sample than the figures indicate. 

The results obtained by this method on mixtures of various sugars 
are consistent enough for all practical purposes, but as a malt prepara- 
tion of known composition is impossible to obtain, we have no way of 
finding out how close the results run on commercial preparations. 

The presence of traces of other sugars may in some cases cause the 
figures to vary slightly from the true amounts, but the results agree very 
well with what one would expect in such preparations from a general 
knowledge of their composition. 

The results are certainly of more practical use than a meaningless 
collection of polarization and copper-reduction figures, 



Cellulose 



Method for Determination of Crude Fiber.— Extract a quantity of 
the substance representing about 2 grams of the dried material with 
ether, using any suitable form of extraction apparatus. To this residue 
in a 500-mil flask add 200 mils of boiling 1.25 per cent solution of sul- 
phuric acid; connect the flask with an inverted condenser, heat at once, 
boiling gently for thirty minutes Filter through silk, and wash with 



ALDEHYDES AND KETONES 623 

hot water until free of acid. Rinse the residue back into the same flask 
with 200 mils of boiling 1.25 solution of sodium hydroxide, boil at once, 
and continue the boiling in the same manner as described above for the 
treatment with acid. Filter through silk and wash with boiling water until 
the washings are neutral. The residue is then transferred on to a weighed 
Gooch. This is best accomplished by spreading the silk filter (which is 
about 18 cm. in diameter, cut and folded like an ordinary filter paper) on 
a watch-glass slightly larger than the silk filter. The residue is then 
gently scraped on the weighed Gooch by means of a small spatula. The 
remaining portion is then rinsed with water, using as little as possible to 
avoid clogging, suction is then applied, and finally washed with alcohol 
and ether. Dry to constant weight at 110°; and weigh, after which 
incinerate completely. The loss in weight is considered crude fiber. 

The solution of sulphuric acid and sodium hydroxide are to be made 
up of the specified strength determined accurately by titration and not 
merely specific gravity. 



CHAPTER XVII 
ORGANIC ACIDS 

ALIPHATIC SERIES 

The organic acids are encountered to a considerable extent in medi- 
cinal chemistry. In the aliphatic series we find the monocarboxylic acids 
of the formic and acetic group of the homologous series C„H2 n +iCOOH, 
the oxidation products of the glycols which are hydroxy carboxylic or poly- 
carboxylic, and unsaturated acids of both kinds. 

The fatty acids of the general formula C«H2n+iCOOH may be 
regarded as derivatives of the paraffins, alcohols, or aldehydes. 

HCH3-HCH2OH -HCHO -HCOOH - 

The grouping -Of is known as the carboxyl and is characteristic 
X)H 
of them all. 

At ordinary temperatures, the lower members of the series are color- 
less liquids except acetic acid, which solidifies at 16-17°, and are miscible 
with water, alcohol, and ether in all portions. As the molecular weight 
increases they become oily in character. The pungency disappears and 
they are less readily soluble in water. The higher members are waxy or 
unctuous solids, with a faint odor and insoluble in water. They are all 
volatile with steam except the higher members, which, however, may 
be distilled in superheated steam. The specific gravity decreases and 
the boiling- and melting-points increase as the series is ascended. It 
should be noted, however, that acids with an odd member of carbon atom 
melt at a lower temperature than the preceding members containing an 
even member. 

These acids are quite stable and are only oxidized with difficulty. The 
lower members decompose carbonates, dissolve metals and metallic hydrox- 
ides, but these acid properties soon disappear and the higher members 
are with difficulty recognized as acids by the ordinary tests. The metallic 
salts of the lower members are soluble in water, but on passing up the series 
the solubility decreases, and in the case of the higher acids only the 
alkali salts are soluble. Many of the salts of the higher acids are soluble 
in ether. The fatty acids react with alcohols, especially in the presence 

624 



ORGANIC ACIDS 625 

of dehydrating agents, forming ethereal salts and water. When treated 
. with phosphorus pentachloride they yield acid chlorides, which interact 
with hydroxy compounds to produce ethereal salts, with ammonia to 
give amides, and on distillation with an alkali salt of a fatty acid to pro- 
duce anhydrides. 

C 2 H5COOH+PCl5 = C2H 5 COCl+POCl3+HCl 

C2H 5 COCl+CH 3 OH=C 2 H 5 COOCH3+HCl 

C2H5COCI+NH3 = CH3CONH2+HCI 
C 2 H5COCl+C2H5COOH = (C2H 5 CO)20+KCl 

The organic acids and their derivatives will be encountered in a large 
percentage of the mixtures analyzed by the chemist in this line of work. 
Often they are subsidiary products to which no attention need be paid, 
again the crucial feature of an analyis will depend upon their accurate 
identification and determination, either as a measure of some parent 
product of which they are a part, or as a measure of their therapeutic 
efficiency, and still again their influence as contaminating features in 
the determination of other substances must be considered. 

In the aliphatic series the acids which are used for their medicinal 
properties include formic, valerianic, agaricic, citric, tartaric, lactic, 
angelic, and succinic, and to a lesser extent acetic, oleic, and stearic. In 
the aromatic series benzoic, salicylic, and phenolsulphonic acids and their 
derivatives make up an appalling list of medicinal agents. 

Allusion has already been made to the influence of volatile acids on 
alcohol determinations. The identification of some of the acids will 
often give valuable evidence as to the presence of certain drugs; angelic 
acid will indicate angelica root, valerianic acid may denote that valerian 
has been employed, and benzoic and cinnamic acids often will lead to 
the discovery of the aromatic balsams. Again the presence of aliphatic 
acids furnishes additional evidence regarding the use of specific drugs 
in complex mixtures, for instance the simultaneous discoveiy of the 
Sanguinaria alkaloids, and a relatively large amount of acetic acid will 
indicate that fluid extract of Sanguinaria was one of the components of 
the mixture. 

The acids play an extremely important part in the identification of 
fats and oils, and in mixtures where the ordinary constants of the oils 
have become modified or rendered doubtful, the separation of the fatty 
acids is the only means of identifying the original product. Sometimes 
it will be necessary to convert the mixed acids into volatile esters, fraction- 
ate the mixture and then reform the acids. By this means more has been 



626 ORGANIC SUBSTANCES 

accomplished in clearing up the chemistry of cod-liver oil than by any 
other method. 

One general observation regarding the work of the analytical chemist 
in detecting organic acids may not be amiss at this point. In identifying 
the acids by color and precipitation tests it is always advisable to convert 
the suspected individual into a neutral stable salt and to work with an 
aqueous solution of the latter. For instance, it is stated that benzoic 
acid will give a flesh-colored precipitate with ferric chloride, but the analyst 
will usually be disappointed if he attempts to get this reaction by adding 
ferric chloride to a residue or an aqueous solution of the free acid. But 
if he adds sufficient dilute ammonia to dissolve the free acid and then 
evaporates the excess, the aqueous solution will give a copious precipitate 
of the characteristic salt. 

Formic Acid, H'COOH 

Formic acid is a colorless, hygroscopic liquid at ordinary temperatures, 
Specific gravity 1.241 at 0° C, it melts at 8° and boils at 101°. It has 
a pungent, irritating odor, is very caustic, blistering the skin, and is mis- 
cible with alcohol, water, ether, and glycerin. It is acid to litmus, decom- 
poses carbonates, and forms well-defined salts. In some of its reactions 
it resembles the aldehydes, it reduces ammoniacal silver oxide with evolu- 
tion of carbon dioxide. When mixed with concentrated sulphuric acid 
it is rapidly decomposed into carbon monoxide and water, this reaction 
distinguishing it sharply from the other acids of the aliphatic series. All 
metallic formates have the same property. Formic acid and formates 
reduce mercuric chloride to mercurous chloride, and this property is 
available for their determination. On adding magnesium ribbon to formic 
acid, hydrogen is evolved and the acid is reduced to formaldehyde, which 
can be recognized by the morphin sulphuric acid reaction. 

Formic acid can be removed completely from an aqueous solution by 
distillation, but like hydrochloric acid it forms a definite hydrate which 
has a definite distillation point, and can never be completely separated 
from water by distillation. 

As ordinarily used it will be found in 25 per cent solution and the 
acid content can be determined by direct titration with normal acid. 

Formic acid is the essential ingredient of the treatment for rheumatism 
known as the " bee sting " remedy. It is also used as an antiseptic, 
diuretic, and tonic, but it is too irritating for general use. Sodium formate 
is employed for the purposes above mentioned, and also hypodermically 
in surgical tuberculosis. It is sometimes dispensed with Adonis vernalis 
(false hellebore) for pneumonia. 

The metallic formates are all soluble in water, but the lead and silver 



ORGANIC ACIDS 627 

salts are only moderately soluble; they are all decomposed by warm 
concentrated sulphuric acid with evolution of carbon monoxide, and by 
dilute acids yielding formic acid. The alkali formates are deliquescent 
and when heated to 250° they are converted to oxalates with evolution 
of hydrogen. When ammonium formate is strongly heated, it is first 
converted into formamide and then to hydrogen cyanide. 

HCOONH4 = H '• CONH2+H2O 

HCONH 2 = HCN+H 2 

Silver formate is precipitated in colorless crystals on adding silver nitrate 
to a concentrated solution of alkali formate, but it is unstable and darkens 
quickly. 

The detection of formic acid or a formate is accomplished by adding 
a slight excess of phosphoric acid to the suspected sample and distilling 
with steam, the distillate being collected in a receiver containing water 
and barium carbonate. The distillate is then evaporated to drive off 
any volatile constituents, aldehydes, etc., diluted with water and filtered. 
Portions of the filtrate are then tested with ammoniacal silver oxide and 
mercuric chloride for the characteristic reductions, and another portion 
evaporated to dryness in a test-tube and warmed very gently with con- 
centrated sulphuric acid and the escaping gas tested with a flame; carbon 
monoxide will ignite and burn at the mouth of the tube. 

The detection and determination of formates will sometimes be of 
moment in the identification of chloral. 

For the determination of formic acid in fruit juices Seeker has modified 
Finkes method slightly. The results obtained are accurate and the pro- 
cedure can be used with medicinal products. 

In the case of free formic acid this method can be used without modi- 
fication, but if the qualitative examination indicated a formate, phosphoric 
acid should be substituted for tartaric. 

The apparatus required consists of a steam generator S, a 
300-mil flask A in which the sample is placed, a 500-mil flask B, con- 
taining a suspension of barium carbonate, a spray trap T, a condenser, 
and a 1-liter graduated flask C. The tip of the tube D, leading into B, 
consists of a bulb containing a number of small holes to break the vapor 
into small bubbles. 

For thin liquids like fruit juices, use 50 mils. For heavy liquids and 
semi-solids like sirups and jams, use 50 grams diluted with 50 mils of 
water. Place the sample in the flask A, add 1 gram of tartaric acid, 
and connect as shown, the flask B having been charged previously 
with a suspension of 2 grams of barium carbonate in 100 mils of water. 
If much acetic acid is present, sufficient barium carbonate must be used 



628 



ORGANIC SUBSTANCES 



so that at least 1 gram remains at the end of the operation. Heat the 
contents of flasks A and B to boiling and distill with steam from the gener- 
ator S, the vapor passing first through the sample in flask A, then through 
the boiling suspension of barium carbonate in B, after which it is con- 
densed, and measured in the graduated flask C. Continue the distillation 
until 1 liter of distillate is collected, maintaining the volume of the liquids 
in the flasks A and B as nearly constant as possible by heating with small 
Bunsen flames, and avoiding charring of the sample in the flask A. After 
1 liter of distillate has been collected, disconnect the apparatus and filter 
the contents of flask B while hot, washing the barium carbonate with a 
little hot water. The filtrate and washings should now measure about 




150 mils. If not they should be boiled down to that volume. Then 
add 10 mils of the sodium acetate, 2 mils of 10 per cent hydrochloric acid, 
and 25 mils of the mercuric chloride reagent. Mix thoroughly and immerse 
the container in boiling water-bath or steam-bath for two hours. Then filter 
on a tared Gooch, wash the precipitate thoroughly with cold water and 
finally with a little alcohol. Dry in a boiling water oven for thirty minutes, 
cool, weigh, and calculate the weight of formic acid present by multiplying 
the weight of the precipitate by .0975. If the weight of mercurous chloride 
obtained exceeds 1.5 grams, the determination must be repeated, using 
more mercuric chloride reagent or a smaller amount of sample. A blank 
test should be conducted with each new lot of reagents employed in the 
reduction, using 150 mils of water, 1 mil of 10 per cent barium chloride 
solution, 2 mils 10 per cent hydrochloric acid, 10 mils of the sodium acetate, 
and 25 mils of the mercuric chloride reagent, heating the mixture in a 
boiling water-bath or steam-bath for two hours. The weight of mercurous 



ORGANIC ACIDS 629 

chloride obtained in this blank test must be deducted from that obtained 
in the regular determination. 

Acetic Acid, CH 3 COOH 

Acetic acid is the bane of the analyst in determining alcohol in drug 
mixtures. The writer has found it consistently in almost every alcoholic 
distillate, and as nobody has ever investigated the extent of its influence 
on the specific gravity, it has to be eliminated before an accurate determi- 
nation of the alcoholic content can be assured. It is probable that in a 
great many instances its influence is negligible. 

Besides occurring as an oxidation product of alcohol, acetic acid occurs 
in drug products to a large extent as a vehicle; as a medicine pure and 
simple, the chief employment of glacial acetic acid is as a vesicatory and 
for removing warts and corns. It is sometimes used as a substitute for 
cantharides where a speedy blister is desired. 

Acetic acid is employed in the preparation of pharmaceutical products 
known as vinegars, of which the most important include cantharides, 
ipecac, opium, squills, Colchicum, Lobelia, Sanguinaria, and the aromatic 
vinegar consisting of several aromatic oils in alcohol and dilute acetic 
acid. Acetic acid also occurs in fluid extract of ergot, Nux Vomica, and 
Sanguinaria. 

The dilute acid is used as an excitant in syncope, asphyxia, and head- 
ache, where the vapors are applied to the nostrils. Camphorated acetic 
acid is an old remedy composed of camphor, alcohol, and dilute acetic 
acid. It is recommended in fainting and nervous debility. 

Pure, anhydrous acetic acid is a crystalline solid, melting 16 • 5°, boiling 
at 118°, with a pungent, penetrating odor and a burning action on the 
skin. It is inflammable when near its boiling-point and burns with a 
feebly luminous flame. It is hygroscopic, miscible with alcohol, water, 
and ether, is an excellent solvent for many organic substances, and for 
certain inorganic elements as sulphur and iodin which do not dissolve in 
water. It is not removed from its aqueous solution by immiscible sol- 
vents, and by this means it may be separated from many of the higher 
acids of the same series, and from the aromatic acids w r ith the exception of 
phenolsulphonic. It is a fairly strong acid, dissolving certain metals and 
metallic oxides, but differs from formic acid in possessing no reducing 
properties and being stable towards sulphuric acid. 

On neutralizing acetic acid with sodium hydroxide and then warming 
the solution with a little sulphuric acid and alcohol, ethyl acetate is formed 
and is readily recognized by its characteristic fruity odor. On adding 
ferric chloride not in excess to free acetic acid a deep-red color soon appears 
which does not disappear on boiling nor yield a precipitate. If the acid 



630 ORGANIC SUBSTANCES 

has been neutralized with sodium hydroxide, or the suspected sample is 
an acetate the same deep-red color is obtained, and on boiling, a heavy 
deposit of basic ferric acetate results. The red color is destroyed by 
hydrochloric or sulphuric acids, differing from that given by meconic acid, 
and it is not soluble in ether as is the case with thiocyanates. Formic acid 
will give a red color, but it has other well-marked reactions differing 
entirely from those of acetic acid, and is readily differentiated. Citric 
and tartaric acids and their salts give only a yellow color with ferric chlo- 
ride, but with Rochelle salts a red color develops on long standing. 

Chlorine, bromin, chromic acid, etc., convert formic acid into carbon 
dioxide, but they do not affect acetic acid in this way. Chromic acid 
is without action on pure acetic acid. 

The normal acetates are all well-defined salts. The silver salt is 
sparingly soluble in water and is precipitated in colorless crystals on adding 
silver nitrate to a concentrated neutral solution of an acetate. The 
double salts of copper acetate and arsenite are insoluble and have a wide 
use as insecticides. 

Lead acetate is used as an astringent, styptic, and sedative. It is 
given for diarrhea, dysentery, and internal hemmorhages, in gonorrheal 
injections, externally as an astringent eye lotion, and as a remedy for 
poison ivy. It will often be found in conjunction with opium and cam- 
phor in diarrhea mixtures, and with zinc acetate or sulphate and the 
Hydrastis alkaloids in astringent washes. 

An aqueous solution of acetic acid may be tested for the presence of 
the acid by neutralizing a portion with sodium hydroxide, concentrating 
and then warming with alcohol and sulphuric acid when the character- 
istic odor of the ethyl acetate is evolved. It will also respond to the test 
with ferric chloride. In such simple mixtures the acetic acid may be 
determined by titration with standard alkali. 

In complex mixtures the acetic acid should be distilled off into an 
aqueous suspension of barium carbonate, and the distillate concentrated 
and then filtered, the filtrate being tested as above. Acetic acid in com- 
bination as acetate may be detected by distilling the mixture with steam 
in the presence of phosphoric acid, running the distillate through barium 
carbonate as described under the determination of formic acid and finally 
filtering off the solution of barium acetate and testing as above. 

Assay of Acetates. — The assaying of acetates may be accomplished by 
distillation in the presence of sulphuric or phosphoric acid. The sample 
is transferred to a distillation apparatus fitted up for steam distillation, 
using a spray trap to connect the distillation flask with the condenser. The 
solution is made up to 100 mils and 5 mils of concentrated sulphuric 
acid added. Distillation is continued until about 600 mils of liquid have 
been collected, and the acid residue reduced to about 20 mils. The dis- 






ORGANIC ACIDS 631 

tillate is titrated with N/10 alkali, using phenolphthalein as an indicator, 
finally boiling the liquid until a faint pink color persists. It is well to add 
a quantity of distilled water to the acid residue and distill over a fraction 
of 100 mils to be sure that all of the acetic acid has been expelled. Cor* 
rect the result by a blank determination. 

Formic acid can be separated from acetic by forming the lead or mag- 
nesium salts, concentrating and adding excess of alcohol in which the form- 
ates are insoluble, while the acetates remain in solution. 

Acetic acid gives three chlor, three bromo, and three iodo- derivatives, 
one of which, trichloracetic acid is employed to some extent as medicine 
and has already been described, see page 593. 

Acetic anhydride is prepared by heating anhydrous sodium acetate 
with phosphorus oxy chloride. 

4CH 3 COONa+POCl3 = 2(CH 3 CO)20+NaP03+3NaCl 

It is a mobile liquid boiling at 137°, with an unpleasant irritating odor. 
It does not mix with water but is soon decomposed, especially on warming, 
giving two molecules of acetic acid. 

The Valerianic Acids 

The Valerianic acids need no other characteristic than their odor to 
assure the analyst of their presence. This odor is characteristic and is a 
conclusive test. Its penetrating and clinging properties are familiar to all 
who have had any experience in drug analysis. Valerianic acid or its esters 
are present in the roots of valerian, angelica and sumbul and in Viburnum 
bark, and the isolation of the acid from liquid mixtures containing drug 
extractive, points to the presence of these drugs. Angelica and sumbul 
contain in addition angelic acid, which has well-defined and character- 
istic properties. 

There are four possible isomerides of the molecular formula C5H10O2, 
but isovalerianic or isopropylacetic acid (CHs^CHCH^COOH, and active 

CH 3 
valerianic or methyl ethyl acetic acid, yCHCOOH are the most im- 

C 2 H 5 X 
portant. The former when pure is a transparent colorless oily liquid, boiling 
175°, miscible in all proportions with alcohol, ether, and chloroform and 
fairly soluble in water from which it may be separated by adding calcium 
chloride. It is the principal valerianic acid obtained from the drugs and 
is also prepared from amyl alcohol. It is used in nervous affections, 
hysteria, and mania. Active valerianic acid is the principal valerianic acid 
obtained from angelica. It boils 172° (a)o -17.85. 



632 ORGANIC SUBSTANCES 

The valerianates are used to a considerable extent in medicine, especially 
the salts of iron, zinc, quinin, and strychnin. These salts are employed 
as sedatives in elixirs and liquid products. They are more or less 
unstable, and are acid in reaction, and give off a strong odor of the acid. 
The acid is readily separated on warming with mineral acid and distilling 
with steam. 

Isovalerianic acid forms a hydrate, C5H10O2H2O, boiling 165°. Iso- 
valerianates are decomposed by acetic, tartaric, and citric acids. Zinc 
valerianate is distinguished from zinc caproate by being soluble in water. 

Nonylic Acids 

Pelargonic or normal nonylic acid, CgHiyCOOH, is formed when 
essential oil of rue is oxidized by nitric acid. It is an oily liquid with a 
faint odor melting 12°, boiling 245°, insoluble in water. The palargo- 
nates with the exception of the alkalies are insoluble in water. 

Myristic Acid 

Myristic acid, C13H27COOH, melts 54°. It occurs in oil of nutmeg, 
probably in combination. 

Palmitic Acid 

Palmitic acid, C15H31COOH, occurs in palm oil as a gly#eride, as an 
ethereal salt, cetyl palmitate, in spermaceti, and as myricyl palmitate in 
beeswax. It is also found combined in other fats and waxes of lesser 
importance, and in the complex resinous constituents of many drugs. 
Palmitin, the triglyceride, occurs in the most liquid fats such as palm 
and cocoanut oil, as well as in butter and human fat. 

The pure acid is a colorless waxy substance, melting at 62° C, soluble 
in alcohol and ether, insoluble in water and decomposing on distillation, 
except in the presence of steam. The alkali palmitates are soluble in 
water and occur in soap. The salts of the other bases are insoluble in 
water, and even the alkali salts are thrown out of acid solution on add- 
ing sodium chloride. 

Margaric Acid, Ci 6 H 33 COOH 

The acid is obtained by boiling cetyl cyanide with an alkali. It was 
formerly supposed to exist as a glyceride in natural fats, but subsequent 
researches seem to prove that the substance obtained at that time was a 
mixture of palmitic and stearic acid. It is a crystalline waxy substance, 
melting 59-60° C. 



ORGANIC ACIDS 633 



Stearic Acid 



Stearic acid, C17H35COOH, occurs as a glyceride in many animal fats, 
especially suet, and in the solid fats generally. The pure acid is a white 
crystalline solid, melting at 69° and resembling palmitic acid in its chem- 
ical and physical properties. Sodium and potassium stearates are soluble 
in water to a clear solution, but on adding a large excess of solvent, the 
acid stearates are deposited in scaly crystals. 

Dioxystearic, Ci7H33(OH) 2 COOH, melting 35°, is. obtained by treating 
dibromisoleic acid with silver oxide. 

Isotrioxystearic, Ci7H32(OH)3COOH, melting 111°, is formed on oxidiz- 
ing castor oil with alkaline permanganate. 

Tetraoxystearic or sativic, Ci7H 3 i(OH) 4 COOH, melting 159-161°, is 
formed on oxidizing linoleic acid with alkaline permanganate. 

Arachidic Acid, C19H39COOH 

The acid in the form of a glyceride is one of the important constituents 
of peanut oil. Its separation and identification is a problem familiar to 
the food chemist, as its presence is used in drawing conclusions as to the 
adulteration of other edible oils, especially olive oil. As it occurs as a 
glyceride in other oils and to some extent in olive, its occurrence is not 
necessarily a conclusion that peanut oil has been used as an adulterant. 

The pure acid occurs in small shiny plates of a pearly luster, melting 
75° C. 

Behenic Acid, C 2 iH 43 COOH 

Behenic acid is found in the oil expressed from the seeds of Moringa 
oleifera (oil of ben). It melts 80-82° and solidifies 79-76°. It has been 
prepared synthetically from erucic acid and then melts 83-84°. This 
acid is of interest as it is used in the preparation of a series of organic 
arsenic compounds for which medicinal virtures are claimed. 

The salts of the bromo and iodo derivatives of behenic acid prepared 
from erucic acid are used as remedies in which it is desired to obtain the 
effects of bromin or iodin. 

Sabromin, Dibrombehenate of Calcium, ^iBLuBroCOOH^Ca 

Sabromin is a colorless, odorless, and tasteless powder claimed to 
contain about 29 per cent bromin and about 3.8 per cent calcium. It 
is insoluble in water and alcohol, soluble in ether, acetone, benzol, ligroin 
and tetrachloride of carbon. On heating on platinum foil it is decomposed 
with liberation of bromin. 



634 ORGANIC SUBSTANCES 



Sajodin, Monoiodobehenate of Calcium, (C 21 H 4 2lCOO) 2 Ca 

Sajodin is a colorless, odorless and tasteless powder, insoluble in water. 
On heating it generates an abundance of iodin vapor; on exposure to 
light the superficial portion becomes yellow without material decompo- 
sition. 

It should contain 26 per cent of iodin and 4.1 per cent of calcium. 

It is used for the same purposes as potassium iodide. 



Ferro- sarjodin 

Basic ferric iodobehenate. Ferro-sajodin has the approximate formula 
(C2iH42lCOO)2(OH)Fe, and containing at least 5 per cent of iron and 
at least 24 per cent of iodin. 

It is a reddish-brown powder, unctuous to the touch, insoluble in water; 
soluble in chloroform and ether, on heating it melts to a brownish-black 
liquid, which emits an abundance of iodin vapors. 

It is indicated in conditions in which iron and iodin are employed, such 
as anemia, rickets, syphilis, chronic bronchitis, arteriosclerosis, etc. 

C erotic Acid 

Cerotic acid, C26H53COOH, occurs in Chinese wax as ceryl cerotate 
an ethereal salt corresponding with cerylpalmitate in spermaceti and in 
beeswax, and in the free state in the Carnauba wax. It no doubt occurs 
in many other waxes whose compositions have not been investigated. 

It is a white powdery substance when pure, melting 78-82° C. 

SOAPS 

The chemistry of soap is intimately connected with that of palmitic 
and stearic acids. 

Soluble soaps consist of sodium or potassium or ammonium palmitate 
or stearate or oleate, or mixtures of these, containing more or less water, 
often perfumed and medicated, and sometimes entirely liquid and con- 
taining ether or some solvent. The soaps with which we are especially 
interested are called medicated soaps. 

The official soap of the Pharmacopoeia is an olive oil soda soap in 
which of course the oleates predominate. Large quantities of soap are 
made from palm and cocoanut oils, stearin, and lard oil. Soaps contain 
varying amounts of water, the better grades little and the cheaper grades 
most. After the amount of water reaches a certain percentage, about 
30 per cent, the soap will float. 



ORGANIC ACIDS 635 

Medicated soaps are offered as remedies for skin diseases, as antiseptic 
washes, and for introducing oxygen into the system. The latter feature 
has come into vogue during very recent years in the so-called " peroxide " 
soaps. 

If a soap contains sufficient medicament to be of value from a thera- 
peutic standpoint, the essential ingredients can be readily detected. The 
sample should be dissolved in water or digested with water until disinte- 
grated, and then treated with an excess of dilute sulphuric acid, and poured 
into a separator and shaken with ether. The metallic bases and any 
alkaloids which might be present will be in the aqueous solution, and the 
fatty acids, phenols, cresols, iodoform, thymol diiodide and similar sub- 
stances will be. dissolved in the ether, and any bran, siliceous material and 
the like will remain undissolved. The acid aqueous solution is then 
drawn off, and a portion tested with a crystal of potassium chromate and 
a little absolute ether, and if peroxide is present a deep blue color will be 
imparted to the ether. The balance of the acid solution is then treated 
with excess of alkali and shaken with ether to remove organic bases which 
should be sought for after evaporating the ether, and the alkaline liquid 
treated with excess of hydrochloric acid and tested for metals, especially 
mercuiy and zinc, and also for borates. 

The ether solution containing the fatty acids, etc., should then be 
shaken with dilute sodium hydroxide, which will remove the acids and 
phenolic bodies, and then separated and the ether filtered, leaving the 
bran behind, evaporated and examined for iodoform, thymol diiodide and 
petrolatum. The alkaline liquid is then treated with excess of hydro- 
chloric acid and shaken with ether, the solvent filtered and cautiously 
evaporated and the residue treated with hot water, the water separated 
and filtered and examined for phenolic bodies, by noting the color given 
by ferric chloride, and precipitating with bromin water. The bromin 
precipitate can be purified and its melting-point determined. 

After a preliminary qualitative test, a quantitative estimation can be 
made along the same lines indicated. Mercury may be precipitated as 
sulphide and weighed, and zinc as sulphide, filtered, redissolved, and pre- 
cipitated as carbonate, ignited, and weighed as oxide. 

As a general thing it can be said of the soaps now in use, that the amount 
of metallic ingredients will be sufficient to give a good quantitative test, 
but that the phenolic bodies are only in minute quantities. 

Some soaps claim iodin as an ingredient, but it is usually in such 
small quantity that its detection is difficult, and its determination of little 
real value. 

Peroxide soaps are much in vogue, and if more than a trace of peroxide 
is present it can readily be detected by the method outlined above. If 
the sample does not respond to this reaction another test should be applied 



636 ORGANIC SUBSTANCES 

with titanium potassium oxalate and any darkening noted. This latter 
reaction must, however, be considered with caution, because it has not yet 
been determined whether other substances present might give this same 
coloration. 

Soap is employed medicinally as a laxative, antacid, and antilithic 
and is often combined with rhubarb in remedies for dyspepsia, consti- 
pation, and biliousness. It has been recommended for urinary calculi, 
but is of doubtful value, though it should be looked for in such prepara- 
tions. It is often found in Hniments combined with opium, camphor, 
and potassium iodide. It is one of the chief constituents of the official 
soap liniment known as " liquid opodeldoc." 

Lead soap, which is really lead oleate, is known as lead plaster, and 
lime soap, lime liniment, or Carron oil, are well-known medicinal agents. 
Ammonia liniment consisting of olive oil partially or wholly saponified 
by ammonia in alcohol, is used for croup and inflammatory conditions 
of the throat. 

Solid opodeldoc is stearin sodium soap containing alcohol. 

Assay of Soap. — The moisture in soap is determined by dissolving 
about .5 gram of the sample accurately weighed in 10 mils of alcohol, and 
evaporating to dryness in tared dish containing 1 gram clean sand, which 
has been previously heated to 110°. The residue is dried at 110° to con- 
stant weight. 

Insoluble impurities and free alkalinity are determined by dissolving 
10 grams in 100 mils of alcohol and filtering any undissolved residue into 
a tared Gooch and washing with hot alcohol. The residue is dried and 
weighed, and represents chloride, carbonate, and silica. It is then washed 
with boiling water, which dissolves the chloride and carbonate, and the 
silica can then be dried and weighed. Free alkalinity can be determined 
in the alcoholic filtrate by titrating with standard acid using phenol- 
phthalein. 

Fatty acids and total combined alkali metals are determined by using 
an alcoholic solution of the soap obtained as above. The alcohol is driven 
off over the steam-bath, the residue taken up with water, transferred to 
a separator, acidulated with sulphuric acid, and shaken with ether. The 
acid liquid is drawn off through a filter into a platinum dish, the filter 
washed, the solution evaporated to dryness and carefully ignited to constant 
weight as sulphate of the alkali metal present. The fatty acids are in 
the ether layer and may be estimated by evaporating the ether in a tared 
dish weighing the residue. 

Assay of Soap Liniment. — Specific Gravity. — Determine this value at 
any convenient temperature. 

Camphor. — Determine rotation in 200-mil tube, using sugar scale. 
Standard soap liniment averages about 65-70 per cent alcohol, and a solu- 



ORGANIC ACIDS 637 

tion of camphor in alcohol of this strength in the proportion of 4.5 grams 
of 100 mils, rotates the scale about 9.5°. 

Alcohol. — Fifty mils are transferred to a distilling flask, diluted to 
200 mils, and 100 mils distilled over. This distillate is transferred to a 
separator, saturated with sodium chloride, and shaken out with low- 
boiling petroleum ether to remove the volatile oils. The balance of the 
determination follows the directions given for determining alcohol in the 
chapter on general methods. Collect the pure distillate in a 100-mil flask. 
The percentage of alcohol corresponding to the specific gravity will be 
half that present in the sample. 

Fatty Acids and Alkali (Anhydrous Soap). — Evaporate the alcohol 
from a 50-mil sample. Transfer to separator, using water, and add a 
slight excess of dilute sulphuric acid. Shake out with ether, collecting 
ether extractions in another separator, washing, and finally evaporating 
to dryness in a tared beaker, the weight being the fatty acids. 

The acid liquid is filtered into a platinum dish, the filter washed, the 
solution evaporated to dryness, cautiously ignited and weighed as sulphate 
of the alkali present. By calculating the alkali to oxide (Na20 or K2O) 
and adding the result to the weight of the fatty acid, the final figures will 
be the quantity of anhydrous soap present. Good soap liniments will 
average slightly over 6 per cent anhydrous sodium soap. 



SEPARATION OF ACIDS OF ACETIC SERIES 

The acids of this series can be separated from each other in several 
ways. The lower members can be separated from the middle and higher 
acids by treating an aqueous mixture with calcium chloride and shaking 
out with ether. By this procedure all of the acids except formic and acetic 
will dissolve in the ether, and on drawing off the aqueous solution and 
washing the ether with a solution of calcium chloride, formic, and acetic 
will be found in the aqueous portion. They can be distilled off with steam 
from the calcium chloride after acidulating with tartaric acid and separated 
from each other by taking advantage of the difference in the solubilities 
of their lead salts in alcohol. 

The ether solution should then be evaporated and the middle members 
separated from the higher by washing out the residue with hot water. 
These acids, which are for the most part volatile, can then be separated 
by the method of partial saturation. The mixture is divided equally and 
one of the portions exactly neutralized with sodium hydroxide; the other 
half is then added and the whole distilled. As the acid strength dimin- 
ishes with the increase in the number of carbon atoms, the lower acid in 
the mixture will displace the higher. For instance, butyric acid will dis- 



638 ORGANIC SUBSTANCES 



place valerianic acid, and if the mixture contained equal quantities of the 
two, the distillate would contain only valeric acid and the residue sodium 
butyrate. If the valerianic acid predominated, the aqueous solution would 
contain both butyrate and valerianate, and when distilled in the presence of 
phosphoric acid, would yield a fresh mixture of the acids which can be 
treated in the same way. If butyric acid were in greater amount the dis- 
tillate would contain both acids and must be again treated by partial 
saturation as before. 

The non-volatile acids may be separated by the fractional precipita- 
tion of their lead, barium or magnesium salts, the insolubility of which 
increases with the number of carbon atoms. The acid mixture is dissolved 
in alcohol and partially precipitated by an alcoholic solution of lead, 
barium, or magnesium acetate, the precipitate consisting largely of the 
acid of highest molecular weight. It is filtered and another precipitate 
obtained from the filtrate, which will consist of acids lower in carbon and 
so on. Each precipitate is then decomposed by hydrochloric acid and 
the new mixture of acids subjected to the same treatment until the sepa- 
rated acids yield constant melting-points. 

Another procedure for separating and determining the identity of the 
higher fatty acids depends on their conversion to their methyl esters and 
fractionating. Bull adopted this procedure when working with the acids 
of cod-liver oil. 



DETECTION AND ESTIMATION OF ACIDS OF ACETIC SERIES WHEN IN 

ADMIXTURE 

The free acids obtained by distillation are saturated by barium car- 
bonate or by the cautious addition of baryta water (using phenolphthalein 
to indicate the point of neutrality), the latter method being preferable 
for the higher numbers of the series. In this way, neutral barium salts 
are formed, which may be obtained in the anhydrous state by evaporating 
off the water and drying the residue at 130°. These barium salts contain 
percentages of barium dependent on the atomic weights of the fatty acids 
present. On moistening the residue with sulphuric acid and then igniting, 
an amount of barium sulphate is obtained proportional to the percentage 
of barium contained in the salt of the fatty acid present. Instead of 
weighing the barium sulphate, a standard solution of baryta water may 
be employed and the weight of barium (or its equivalent of barium sul- 
phate) calculated from the volume of solution employed. This method 
also serves as a useful check on the determination of the weight of barium 
sulphate. The following table shows the proportions of barium contained 
in, and of barium sulphate producible from the barium salts of the lower 
acids of the acetic series: 



,he 



ORGANIC ACIDS 



639 



Name of Salt 


Barium, 
Per Cent 


Barium Sulphate, 
Per Cent 


Barium formate 


70.25 

53.73 

48.41 
44.05 
40.41 
37.33 
34.68 
32.39 
30.38 
28.60 


119.47 


Barium acetate 

Barium propionate 

Barium butyrate 

Barium valerianate 


91.37 
82.13 
74.91 

68.73 


Barium caproate 


63.48 


Barium oenanthylate 

Barium caprylate 


58.98 
55.08 


Barium pelargonate 

Barium caprate 


51.66 

48.64 



From this table it will be seen that the pure barium salts of the lower 
acids of the acetic acids can very readily be distinguished from each other 
by estimating the percentage of barium contained in them. In the case 
of mixtures of two acids the identity of which is established, the propor- 
tions in which the two are present may be calculated from the following 
formula, in which x is the percentage of barium salt of the lower fatty acid 
in the mixed barium salts obtained ; P, the percentage of barium sulphate 
yielded by the mixed barium salts on treatment with sulphuric acids; B, 
the percentage of the same theoretically obtainable from the pure salt of 
the lower fatty acid; and b, the percentage of the same, theoretically 
obtainable from the pure salt of the higher fatty acid. Then 

Bx=100P+bx-100b. 

For example, suppose a mixed barium salt known or assumed to con- 
sist of acetate and valerate to have yielded a precipitate of barium sulphate 
equivalent 78.45 per cent of the weight taken, when treated with sulphuric 
acid and ignited. Then, by the above formula, 



therefore 
and 



91.37s = 7845+68.73s 
22.643 = 972, 
3 = 42.93. 



6873, 



Hence the mixed barium salt consisted of 42.93 of barium acetate, 
and 57.07 of barium valerate. From these data and the weight of mixed 
barium salt found, the actual amounts of acetic and valeric acid may be 
calculated. 



ACIDS OF THE ACRYLIC OR OLEIC SERIES, CnHna-x COOH 

The acids of this series are unsaturated and therefore show marked 
differences from those of the preceding series, but all reactions affecting 



640 ORGANIC SUBSTANCES 

the carboxyl group are analogous. They combine directly with two 
atoms of bromin to form dibrom substitution products of the acids of 
the acetic series, thus oleic acid gives dibrom-stearic acid. When these 
dibrom acids are boiled with alcoholic potash they yield either monobrom 
substitution products of the acrylic series, or both bromin atoms are 
removed as hydrobromic acid and a new acid of the next series (propiolic) 
is produced. 

The higher members of this series are reduced to saturated acids by 
hydriodic acid. 

These acids on fusion with potassium hydroxide are converted to potas- 
sium salts of two members of the acetic series, the acids produced depend- 
ing on the position of the double bond; thus acrylic acid yields acetate 
and formate, and solid crotonic acid two molecules of acetate. 

The higher members are converted into crystalline isomerides by the 
action of nitrous anhydride. 

The Crotonic Acids 

Solid crotonic acid, CH3CH = CHCOOH, forms needles melting 72°, 
boiling 189° C. It is somewhat soluble in water, and has an odor like 
butyric acid, into which it is converted by nascent hydrogen. 

Liquid crotonic acid is apparently a stereoisomeride of the former, 
into which t is converted by heating to 180° C. The boiling-point is 
given at 172°. It is claimed to be present in croton oil. 

Methyl acrylic acid, CH2 = C(CHs)COOH, has been reported as occur- 
ring as an ester in oil of chamomile. It melts 16° and boils 160° C. 

Angelic Acid, CH 2 = CHCH(CH 3 )COOH 

This acid and its isomeride, tiglic or methyl crotonic acid, are impor- 
tant in our work. The former occurs as an ethereal salt in the oils of 
cumin and Roman chamomile and probably other species of Anthemis, 
and in Arnica montana, and also in angelica root. It forms monoclinic 
prisms or needles of a spicy odor, melting 45°, boiling 185°, soluble in 
alcohol, ether, and hot water. It may be obtained by boiling an extract 
of the root with alkali, filtering, acidifying with phosphoric acid, and 
distiUing. 

Tiglic acid, CH 3 CH = C(CH 3 )COOH, an isomer of angelic acid, is a 
liquid, occurs in croton oil, cumin oil, and chamomile, and is also a product 
of decomposition of some of the Cevadilla alkaloids. It apparently occurs 
in croton oil as a glyceride. It is obtained from cumin and chamomile 
oils with angelic acid. It differs markedly from angelic acid in being a 
vesicant, and will quickly produce blisters. 



ORGANIC ACIDS 641 

The identification of angelic acid will not necessarily prove the presence 
of angelica root in a preparation, but if it is found without the accompany- 
ing tiglic acid, which seems to be absent in the drug, but which does occur 
in chamomile and cumin, the presence of angelica is probable. 

Angelic acid may be expected to occur in tonic mixtures, and in some 
cases the angelica will be apparent by its characteristic odor. It will also 
be found in hniments and local absorbents and application for ulcers and 
goiter, where it occurs in some of the tinctures recommended for such 
ailments, with arnica and chamomile. 

OLEIC ACID, C 17 H 33 COOH 

This acid is the most important of the oleic series, and is of interest 
to us because it is the acid constituent of the salt used to make lead plaster, 
and is used for making oleates. It occurs as a glyceride in many fats 
and oils used in ointments and for various other pharmaceutical purposes. 
It is sometimes used as a medicine in biliary colic. 

It is an oily liquid, solidifying at 0°, and melting again at 14° C, 
soluble in alcohol, ether, and chloroform. Under ordinary conditions 
it cannot be distilled without decomposition, but with superheated steam 
it goes over at 250°. On fusion with potassium hydroxide it gives acetate 
and palmitate. Nitric anhydride converts it into isomeric elaidic acid, 
which is a solid at ordinary temperature and melts at 45°. This s called 
the Elaidin test and is often applied to oils. It absorbs oxygen with con- 
siderable readiness, becoming darker in color and as recovered from oils 
as found in commerce, it seldom is in a chemically pure state. 

The alkali oleates are soluble in water, and if a large quantity of the 
solvent is present, insoluble acid oleates are formed. Barium oleate is 
insoluble in water. The lead salt is soluble in ether, differing markedly 
in this respect from the lead salts of the saturated acids. This property 
furnishes a means of separating oleic acid from stearic and palmitic acids. 
On digesting the mixed acids with litharge for an hour at 100° C, and then 
treating with ether, the oleate will dissolve together with small quantities 
of the other lead salts, and on shaking with dilute sulphuric or hydro- 
chloric acid the lead is precipitated and the pure acid recovered from the 
ethereal solution. It should not be taken for granted that an acid obtained 
by this procedure is necessarily oleic acid alone, or even oleic acid at all, 
for the lead salts of many other unsaturated acids occurring in fixed oils 
have not been investigated as yet. 

The oleates are prepared either by treating a metallic oxide or free alka- 
loid with oleic acid, or by double decomposition of a soluble solution of 
sodium oleate with a soluble salt of the metal. 



642 ORGANIC SUBSTANCES 

HYDROXY AND DIBASIC ACIDS OF THE ALIPATHIC SERIES 

These acids may be considered as oxidation products of the glycols, 
and some of them are extremely important in medicinal chemistry, both 
from an analytical and therapeutic standpoint They may be divided 
into four groups. 

1. Hydroxy monocarboxylic acids, of which lactic acid is important. 

2. Dicarboxylic acids, including oxalic and succinic acids. 

3. Hydroxydicarboxylic acids, of which tartaric acid is important. 

4. Hydroxytricarboxylic acids, represented by citric acid. 



Hydroxy Monocarboxylic Acids 

Theoretically the simplest member of the group should be hydroxy 
formic O-H-COOH, or carbonic acid; the acid is not known in the free 
state, but as its anhydride, carbon dioxide. 

CH 2 OH 

! 

Gly collie or hydroxyacetic acid, COOH, is obtained by boiling the 
potassium salt of monochloracetic acid with water. 

CH 2 ClCOOH-J-HOH = CH2OH+HCI. 

I 
COOH 

It is also produced on oxidizing glycol and by treating amido acetic acid 
with nitrous acid. 

Glycollic acid is a crystalline hygroscopic substance, melting 80°, and 
readily soluble in alcohol, water, and ether. It has both acid and alcoholic 
properties, neutralizing carbonates and forming salts, oxidizing to the 
aldehyde acid glyoxalic acid, and on further oxidation to oxalic acid. When 
the carboxyl group is esterified the hydroxyl may still be displaced by 
alkali metals and the acetyl group. When heated with sulphuric acid 
it is decomposed into formaldehyde and formic acid. 

Lactic Acids 

There are two lactic acids, a-hydroxypropionic or ethylidene lactic 
acid, CH3CHOHCOOH, and /3-hydroxy propionic, ethylene lactic or 
hydracrylic, CH 2 (OH)CH 2 COOH. 

The former exists in three modifications, dextro, lsevo, and inactive, 
and the inactive is known as fermentation lactic acid, the commonly 
occurring acid, and is formed during the fermentation of sugar, starch, 
etc., in presence of nitrogenous animal matter, and is present in sour milk. 



ORGANIC ACIDS 643 

It will seldom if ever be found in the pure isolated state, but occurs as a 
thick syrupy aqueous solution, miscible with water, alcohol, and ether, 
but not with chloroform. It cannot be distilled, and is readily broken 
up on warming with dilute sulphuric acid, yielding acetaldehyde and 
formic acid. It functionates as an acid and a secondary alcohol. It 
forms metallic and ethereal salts, and the salts themselves will react with 
acetyl chloride with reactions affecting the hydroxyl group; it acts like 
a secondary alcohol giving a-brom propionic acid with hydrobromic acid, 
CH3CHOHCOOH+HBr = CH 3 CHBrCOOH+H 2 0, and propionic acid 
with hydriodic acid, the a-iodo acid first produced being reduced, 

CH3CHICOOH+HI = CH3CH 2 COOH+I 2 

On oxidation with permanganate it is converted into pyruvic acid, a keto 
acid. 

CH3CHOHCOOH+O = CH3COCOOH+H2O - 

Nitric acid converts lactic acid to c :ialic acid, and chromic acid produces 
acetic acid, carbon dioxide, and water. 

Most of the lactates are soluble; the zinc and calcium salts are crys- 
talline and soluble in hot water. It does not give a precipitate with lead 
acetate. The zinc salt is precipitated when zinc sulphate is added to 
lactic acid neutralized with ammonia. Salts of the type CH3CHOMCOOM 
are known, thus sodium sodio-lactate is prepared by the action of sodium 
on sodium lactate. The combination of lactates with phosphates known 
as lac to phosphates, have an extensive use in medicine. 

Copper phosphate produces a deep-blue solution but no precipitate. 
The strength of the commercial acid is about 75 per cent, and when heated 
to 150° it is largely converted into a substance called concrete lactic acid 
or lactide, which is probably an anhydride. It has considerable solvent 
action on calcium phosphate, and is therefore used to remove tartar from 
the teeth. 

Lactic acid can be titrated directly with alkali hydroxides, using phenol- 
phthalein. When lactic acid syrup is evaporated at the ordinary temper- 
ature in dry air as in a desiccator, the anhydride and lactide are gradually 
formed, the same results occur when the acid is heated above 130° C. 
These substances are nearly insoluble in water, but are reconverted into 
lactic acid on boiling with water, or when treated with alkali hydroxides. 
In commercial lactic acid the anhydride commonly runs up to 10 per cent. 

Concentrated sulphuric acid does not blacken lactic acid in the cold, 
and on warming the mixture turns brown with copious evolution of carbon 
monoxide. When heated with dilute sulphuric acid, acetaldehyde and 
formic acid are evolved. When distilled with calcium oxide, carbon 
dioxide and ethyl alcohol are evolved. 



644 ORGANIC SUBSTANCES 

Lactic acid gives a lead salt which is soluble in water, and a barium 
salt soluble in alcohol. Zinc lactate is insoluble in alcohol. 

A dilute solution of lactic acid on distillation with sulphuric acid and 
potassium bichromate yields formic acid and acet aldehyde. If the dis- 
tillate is conducted through barium carbonate as detailed under the 
Determination of Formic Acid, the presence of the latter can be detected, 
and the aldehyde identified in the final distillate. 

If a weak solution of the pure acid is heated to 100° with concentrated 
sulphuric acid for two minutes, portions of the product will give a rose-red 
color with alcoholic solutions of guaiacol, and an orange-red with alcoholic 
codein. The color is due to acetaldehyde. Glycollic acid would give 
formaldehyde and hence different coloration. 

Commercial lactic acid is tested for its content of free acid and anhy- 
dride by the following methods: 

Free Acid. — Twenty grams are diluted to 250 mils and 25 mils of the 
dilute solution titrated direct, as rapidly as possible in the cold with N/5 
alkali, using phenolphthalein. One mil =.0181 gram lactic acid. The 
end-point is reached when a pink color appears, which remains on stirring. 

Anhydride. — Twenty-five mils of the same solution are boiled with a 
known excess of N/5 alkali for ten minutes, and after adding sufficient 
N/5 acid to neutralize the alkali, the excess of acid is titrated back with 
alkali. The difference between the first and second determinations gives 
the anhydride. 

The determinations of lactic acid and lactates in pharmaceutical mix- 
tures is still a problem of research. There are undoubtedly assay methods 
which give fairly accurate indications of the percentage values of the pure 
substances, but they are not applicable to mixtures. 

Inactive lactic acid can be separated into the two modifications by 
the difference in solubility of the strychnin or morphin salts, the laevo 
form being the least soluble. 

Dextro or sarcolactic acid occurs in juices of muscular tissue and in 
certain body excretions. Its anhydride and salts are laevo rotatory. It 
is almost completely precipitated from its solution by copper sulphate, 
while inactive lactic acid yields a deep-blue liquid. 

The lactic acids give the iodoform reaction. 

Ethylene Lactic Acid or Hydracrylic Acid 

This acid is also found in meat juices and is distinguished from ethyl- 
idene lactic acid in yielding no anhydrides, but acrylic acid and water when 
heated. When oxidized it yields carbon dioxide and oxalic acid. Its 
zinc salt is very soluble in water. 

Lactic acid is used as a remedy for dyspepsia, diarrhea, diabetes, the 



ORGANIC ACIDS 645 

removal of phosphate in the urine, the removal of false membranes as 
in diphtheria and croup, in tuberculous affections of the mouth and throat, 
and for removing tartar from the teeth. It is also combined with pepsin,, 
as it is supposed to increase the solvent power of the ferment on food. 

Lactic acid is sometimes used in the form of sticks which consist of the 
acid and menthol held in a gelatin base. 

It is largely dispensed in syrups and elixirs, combined with alkali 
metals and calcium. 

The most important salts medically are those of calcium, magnesium, 
sodium, potassium, and hthium. 

Zinc lactate has been employed in epilepsy, and mercury and silver 
lactates in diseases of the mucous membrane. 

Glycerol mono- and di-lactates are used medicinally. 

A compound of lactic acid and santalol is prepared by heating the 
acid and oil of sandalwood at 130-140° for several hours. The product 
is purified by washing with water, bicarbonate and hydrochloric acid. It 
is a reddish-brown liquid, insoluble in water, but soluble in organic solvents. 

Estimation of Lactic Acid in Lactates. — The method which gives good 
results in some cases where other methods are either useless or too trouble- 
some, depends upon the oxidation of lactates in sulphuric acid solution, 
by means of standard potassium bichromate solution, when the following 
reaction takes place; 

3C 3 H 6 03+2K2Cr207+8H2S0 4 

= 2K2S04+2Cr2(S04)3+3C2H402+3CQ2+llH 2 0. 

An accurately weighed quantity of the material (about .4 gram), or an 
aliquot part of the solution after having been made up to a definite volume, 
is, after suitable dilution, boiled gently for one hour with 10 mils of 10 
per cent sulphuric acid and 25 mils of N/2 potassium bichromate in an 
Erlenmeyer flask, fitted with a reflux condenser. The excess of potassium 
bichromate is titrated in the usual manner with N 10 sodium thiosulphate 
after the addition of 10 mils of 10 per cent potassium iodide and 1 drop 
of starch paste. One mil N/2 potassium bichromate corresponds to .01127 
gram of lactic acid. 

If volatile matters which reduce chromic acid are present, they must 
be first removed by repeated evaporation. The presence of sugar, dextrin 
and similar materials renders this method useless, as they reduce chromic 
acid, and, moreover, cannot be separated. Good results are obtained with 
mixtures of double salts such as antimony calcium lactate and antimony 
sodium lactate, containing more or less great excess of free lactic acid. In 
this case, the antimony is first precipitated as sulphide by means of sulphur- 
etted hydrogen, excess of the latter being subsequently expelled by boiling. 



646 



ORGANIC SUBSTANCES 



Lactic anhydride is not oxidized by the above treatment, and if present 
must be first converted into lactic acid by heating with a slight excess of 
alkali. 

DICARBOXYLIC ACIDS 

The relationship of the acids of this class is shown by the following: 



COOH 

1 


COOH 

1 


COOH 
1 


COOH COOH 

/ 1 


COOH 

1 


COOH 

1 


COOH 


CH 2 


CH 2 


CH3CH CH 2 


CH 2 


(CH 2 ) 7 


Oxalic 


1 


1 


\ i 


1 


1 




COOH 


CH 2 


COOH CH 2 


CH 2 


COOH 




Malonic 


I 


Isosuccinic 1 


| 


Azelaic 






COOH 


CH 2 


CH 2 








Succinic 


1 
COOH 

Glutaric 


1 
CH 2 

1 
COOH 

Adipic 





Oxalic acid is not of importance therapeutically, but its salts occur 
in certain plants, and its identity may be important in establishing the 
presence of a certain drug. Succinic acid and the succinates are used in 
medicine. The other acids are of interest to us only from their chemical 
relation to the group as a whole. 



Oxalic Acid 

Oxalic acid forms colorless crystals containing two molecules of water, 
readily soluble in alcohol and water, and sparingly in ether. It melts at 
100°, losing its water, and at 150° sublimes. When heated to a higher 
temperature it is decomposed into formic acid and carbon dioxide, or 
to carbon monoxide, dioxide, and water. When heated moderately with 
concentrated sulphuric acid it is decomposed and gives the final products 
as above. It has reducing properties, precipitating gold, and is readily 
oxidized by permanganate. 

It is dibasic and forms salts with two equivalents of the metallic 
hydroxide, or with two molecules of a monohydric alcohol. It has fairly 
strong acid properties, decomposing carbonates and dissolving certain 
metallic oxides. The alkali oxalates are soluble in water, the acid alka- 
line salts and silver salts less so, and most of the other salts are insoluble 
or only sparingly. 



ORGANIC ACIDS 647 



Succinic Acid 



Succinic acid crystallizes in colorless prisms, melting 180-182° and 
subliming readily. It is sparingly soluble in water, alcohol, and ether, and 
insoluble in chloroform and benzol. When strongly heated it forms the 
anhydride and the vapors produce coughing. It is very stable and little 
affected by oxidizing agents. It often sublimes without charring when 
strongly heated. When a soluble succinate is treated with ferric chloride, 
a rich brown precipitate is produced which might at first be mistaken 
for the precipitate given by benzoic acid. A solution is not precipitated 
by calcium or bar urn chlorides. 

Sodium succinate is used as a saline cathartic, and also in combating 
infections of the gall bladder and biliary tract. 

CH 2 CO x 

Succinic anhydride, | }0, is prepared by heating the acid with 

CH 2 CCK 
phosphorus oxy chloride for some time and then distilling. It is a color- 
less crystalline substance, melting 120°, and when boiled with water or 
an alkali is reconverted to the acid or a succinate. It is used in the prepa- 
ration of succinic peroxide, the chemistry of which has been described 
unde Peroxides. 

Succinic acid can be determined b}^ shaking out with ether from a 
solution acidulated with mineral acid, and weighing the residue left on 
evaporation. 

Ammonium succinate is used as a diuretic and an antispasmodic in 
cramps, hysteria, and delirium tremens. 

Isosuccinic acid melts 130°, and sublimes readily. It does not form 
an anhydride and when heated alone, or with water, it is decomposed 
into propionic acid and carbon dioxide. 

Identification of Succinic Acid — Treat .1 gram acid with .5 gram para- 
toluidin in a test-tube fitted with a cork stopper and an air cooler and heat 
for one-half hour in an oil-bath at 200-220°. Cool partially and add 
10 mils dilute alcohol (1-1) and boil. Cool well and filter the succin- 
toluide. Wash with 2 mils alcohol (1-1), crystallize from 5 mils boiling 
strong alcohol, filter, wash with 1 mil strong alcohol, dry at 100° and 
determine the melting-point, which should be 254.5-255.5° C. 

Asparaginic, aspartic, or aminosuccinic acid, COOHCEkCHXNHs)- 
COOH, results when asparagin is boiled with acids or alkalies. It is 
sparingly soluble in cold water and alcohol, is readily soluble in hot water 
and alkalies. Asparagin occurs in many plants, but it has practically 
no use medicinally. 



648 . ORGANIC SUBSTANCES 



HYDROXYDICARBOXYLIC ACIDS 

In this group we find malic and tartaric acids, the former of special 
interest to the food chemist, and the latter to the drug chemist. 

TARTARIC ACID 
COOH 

CHOH 

I 
CHOH 

I 
COOH 

Tartaric acid is extensively used in medicine. It is a refrigerant and 
an antiscorbutic, and in combination with alkalies is a mild laxative and 
diuretic. It enters into the combination of artificial effervescent mineral 
water salts and will sometimes be found in granular effervescent prepara- 
tions together with citr c acid. 

Seidlitz mixture consists of sodium and potassium tartrate (Rochelle 
Salt), sodium bicarbonate, and tartaric acid. Effervescent salts of the 
Carlsbad type contain sodium bicarbonate, tartaric acid, and sugar; of 
the Kissingen type, potassium and sodium chloride, magnesium sulphate, 
bicarbonate, acid, and sugar; of the Vichy type, sodium chloride, mag- 
nesium sulphate, potassium carbonate, sodium bicarbonate, acid, and 
sugar. As the bitartrate of potassium it will be found in combination 
with sulphur, and sometimes with camphor, opium, and Asclepias tube- 
rosa; and with ipecac, arsenous acid, sodium benzoate, and Capsicum. 

Tartaric acid should be 'ooked for whenever antimony is found, as it 
forms with this latter an important double salt known as Tartar Emetic. 
The various combinations containing this substance are described more 
fully under Antimony. 

Tartaric acid exists in several forms, and their study from the point 
of view of stereoisomerism has been exhaustively considered and detailed 
at length in works on theoretical organic chemistry. These forms include 
the dextro, laevo, racemic or uvic, and meso. The racemic and meso 
are inactive, and the racemic can be resolved in both dextro and laevo by 
appropriate means, but the meso cannot. The dextro is the acid of common 
occurrence and is the form in which we are interested from an analytical 
standpoint. 

The pure acid forms anhydrous, colorless, transparent rhombic prisms, 
melting 168-170° C. but not sharply as decomposition takes place. Specific 
gravity 1.74-1.75. It is readily soluble in water and alcohol, very slightly 



ORGANIC ACIDS 649 

in ether, and almost insoluble in chloroform and benzol. It chars with 
sulphuric acid or when slowly ignited, emitting the odor of burnt sugar. 
When heated some time at 150° it gives the anhydride and other com- 
pounds. 

Neutral potassium salts give a crystalline precipitate with free tartaric 
acid, insoluble in acetic acid, but dissolving in mineral acids and alkalies. 
This precipitation is prevented if boric acid is in solution, which must be 
borne in mind when tablets are being tested, as boric acid is often present 
in tablets as a lubricant. 

A solution of the free acid nearly neutralized with ammonia should 
give no precipitate with calcium sulphate. Oxalic and racemic acids will 
give a precipitate with this test. 

When warmed in the presence of ammoniacal silver oxide, a silver 
mirror is deposited on the walls of the containing vessel. 

Cinchonidin sulphate gives a white crystalline precipitate with free 
tartaric acid or its ammonium salt. 

When a neutralized solution of tartaric acid is treated with a calcium 
salt, a precipitate is thrown down which is soluble in potassium hydroxide 
but which comes down again on boiling. The precipitate is also soluble 
in ammonium chloride. Calcium racemate is insoluble in acetic acid 
and nearly so in ammonium chloride. 

Tartaric acid is broken up into the acetate and oxalate on fusion with 
potash. Nitric acid oxidizes it to oxalic acid. Tartaric acid in solution 
prevents the precipitation of iron and aluminum by alkalies. 

Tartaric acid reduces alkaline permanganates. 

The important salts of tartaric acid are the following : 

Sodium and potassium tartrate. Rochelle salt or Seignettes salt. 

Potassium antimonyl tartrate. Tartar emetic. 

Potassium hydrogen tartrate. Cream of Tartar. 

Salt of tartar is a misleading name applied to potassium carbonate. 

When barium chloride is added to a solution of tartar emetic a pre- 
cipitate is formed according to the equation. 

2KSbOC4H406+BaCl2 = Ba(SbOC4H40 6 )2+2KCl. 

The barium salt on decomposition with sulphuric acid gives an acid 
solution which soon deposits antimonous hydroxide, but if it is neutralized 
with potassium hydroxide before decomposition occurs it yields tartar 
emetic. It would indicate that the emetic was the potassium salt of a 
tartaric antimony acid, which has been called tartryl antimonous acid, 
and hences the emetic would be potassium tartryl antimonite. 

When SD2O3 is dissolved in tartaric acid, antimonyl tartrate (SbO)2- 
C4H4O6 is produced, and crystallizes from the solution on adding alcohol. 



650 ORGANIC SUBSTANCES 



When this is boiled with normal potassium tartrate it is converted 
tartar emetic, (SbO) 2 C4H406+K2C4H40 6 = 2KSbOC4H406. 

Anilin antimony tartrate, GiHsOeSbOCeHyN, is soluble in water, 
sparingly in alcohol, gives a violet color with calcium chloride, a white 
precipitate with hydrochloric acid, soluble in excess and a white precipi- 
tate with nitric acid soluble in large excess. 

Cobalt nitrate solution gives a red color when added to an alkali tar- 
trate, the coloring being discharged on adding excess of sodium hydroxide. 
If the alkaline solution is boiled a deep-blue color appears on again 
heating. Alkali citrates give an immediate deep-blue color in the cold 
with cobalt nitrate in the presence of alkali. 

Tartar emetic does not behave like other tartrates with cobalt nitrate, 
the reaction being similar to that obtained with citrates. 

A solution containing free tartaric acid yields a crystalline precipitate 
in the cold with 10 per cent solution of calcium formate, having a character- 
istic microscopic appearance. Citric acid gives no reaction in the cold, 
but on warming, a crystalline precipitate is obtained. 

Detection of Tartaric Acid in Mixtures. — An aqueous solution of the 
product is precipitated with excess of lead acetate and the precipitate 
filtered, washed with water, and 50 per cent alcohol until free from lead, 
and the precipitate decomposed by hydrogen sulphide in the presence of 
a little ammonia. The solution is filtered from the lead sulphide and boiled 
to expel the excess of ammonia, and any ammonia sulphide formed, 
filtered again if any sulphur is precipitated, and portions tested as follows : 

Ammoniacal silver oxide will give a silver mirror on warming; calcium 
chloride gives a precipitate in the cold, becoming granular on boiling and 
soluble in acetic acid; cinchonidin sulphate gives a precipitate of white 
needles not always appearing at first but gradually appearing as the solu- 
tion stands. 

The accompanying table shows the comparative reactions of the free 
hydroxy acids and their salts. 

Determination of Tartaric Acid. — Tartaric acid when it occurs by 
itself can be estimated without difficulty, and when it occurs simultane- 
ously with citric .acid the potassium method will give good results. The 
accurate determinations of citric acid in presence of tartaric acid is still 
a matter for study. 

Tartaric acid in an aqueous solution can be titrated directly with 
alkali using phenolphthalein as an indicator. 

Tartaric in mixed preparations can be determined with fair accuracy 
by the method recommended for the determination of the total acid in 
wines. The method of the Association of Official Agricultural Chemists 1 
is quoted herewith: 

» Jour. A. 0. A. C, Vol. 1, p. 240. 



to 



ORGANIC ACIDS 



651 



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652 



ORGANIC SUBSTANCES 



Neutralize 100 mils of the wine with N/1 sodium hydroxide, calculating 
from the ac dity, as determined by titration, the number of mils of N/1 
alkali necessary for the neutralization. If the volume of the solution 
is increased more than 10 per cent by the addition of the alkali, evaporate 
to approximately 100 mils. Add to the neutralized solution .075 gram 
of tartaric acid for each mil of N/1 alkali added and, after the tartaric 
acid has dissolved, add 2 mils of glacial acetic acid and 15 grams of potas- 
sium chloride. After the potassium chloride has dissolved, add 15 mils of 
95 per cent alcohol by volume, stir vigorously until the potassium bitar- 
trate starts to precipitate, and then let it stand in an ice box for at least 
fifteen hours. Decant the liquid from the separated potassium bitartrate 
on a Gooch, prepared with a very thin film of asbestos, or on filter paper 
in a Buchner funnel. Wash the precipitate and filter three times with a 
few mils of mixture of 15 grams of potassium chloride, 20 mils of 95 per 
cent alcohol by volume and 100 mils of water, using not more than 20 mils 
of the wash solution in all. Transfer the asbestos or paper and precipi- 
tate to the beaker in which the precipitation was made, wash out the Gooch 
or Buchner funnel with hot water, using about 50 mils in all, heat to 
boiling and titrate the hot solution with N/10 sodium hydroxide, using 
phenolphthalein as an indicator. Increase the number of mils of N/10 
alkali required by 1.5 mils to allow for the solubility of the precipitate. 
One mil of N/10 alkali is equivalent, under these conditions, to .015 gram 
of tartaric acid. Subtract the amount of tartaric acid added from this 
result to obtain the grams of total tartaric acid per 100 mils of wine. 

Method Using Calcium Chloride. — Dissolve 5 grams of the tartrate- 
containing body in hydrochloric acid, filter if necessary. Neutralize with 
sodium hydroxide free from carbonate, add an excess calcium chloride, 
and after allowing to stand for some time collect the precipitate on a 
filter. Wash, dry, ignite, titrate with N/1 hydrochloric acid. Every 100 
mils of N/1 acid required to neutralize CaO or CaC03 resulting from the 
ignition represents 7.5024 grams H2C4H4O6. 

Kling and Florentine l have proposed a method for determining tar- 
taric acid which they claim is of special application when working with 
products containing iron, aluminum, and antimony. Ammonium citrate 
is employed to replace the tartaric in its combinations with the metals 
mentioned. The following solutions are required: (a) Ammonium citrate 
5 per cent; (b) ammonium Z-tartrate free from d-tartrate, 2 per cent, 
preserved with 5 mite formaldehyde; (c) calcium acetate prepared by 
dissolving 16 grams calcium carbonate in 120 mils acetic acid and making 
up to 1 liter; (d) hydrochloric acid containing 40 grams at 22° B., per 
liter; (e) 5 grams calcium carbonate dissolved in 20 grams acetic acid 



Orig. Com. 8th Intern. Congr. Appl. Chem., 1, 237; Bui. Soc. Chem., 11, 886. 



ORGANIC ACIDS 653 

with 100 grams of sodium acetate per liter; (/) potassium permanganate, 
1.6 per cent, standardized against a known solution of tartaric acid. 

The tartaric acid is estimated by dissolving the sample in 150 mils 
water and treating the solution with 10-15 mils of solution (a), then 
25 mils of solution (b), and 20 mils of solution (c), mixing and allowing 
to stand for twelve hours. It is then filtered, washed with cold water, 
and the precipitate transferred into another container, using 20 mils of 
solution (d) which dissolves the racemate, made up to 150 mils; 40-50 
mils of solution (e) added and heated to 80° C. on a water-bath. When 
the solution has cooled and the precipitate settled, it is filtered, washed, 
dissolved in 10 per cent sulphuric acid, and titrated with permanganate. 
The factor obtained for tartaric acid in the racemate is divided by two 
and the amount of ^-tartaric in the original solution determined. 

Analysis of Granular Effervescent Salt. — Make a thorough admix- 
ture of sample, separate about 15 grams powder in a mortar and transfer 
to a weighing bottle. 

(1) Weigh out exactly about 1 gram and determine the total CO2 in 
absorption apparatus. Calculate to sodium and potassium bicarbonates. 

(2) Determine phosphoric acid in .5 gram and calculate to sodium 
phosphate, Na 2 HP0 4 2H 2 0. 

(3) Determine chlorine in 1 gram and calculate to sodium chloride. 

(4) If magnesium is present determine in 1 gram and calculate to 
magnesium sulphate, MgSC^TEbO. 

(5) Determine sulphate in 1 gram and calculate to MgSQiTH^O, and 
if any excess calculate to Na2SO4l0H 2 O. 

(6) Dissolve 1 gram in water, boil, and titrate. If acid, calculate to 
mixed citric and tartaric acids. This figure will give the acid in excess 
of that necessary to neutralize the bicarbonates. To determine the amount 
used up by the bicarbonates, figure back from the results obtained in Xo. 
1. This amount plus the amount found in excess will give the total acids. 
The final figure is of course only approximate, but it will often come out 
within 1 to 2 per cent of the quantity known to have been added. There 
is no method of determining the relative quantities of citric and tartaric 
acids in a mixture of the two. 

If the sample is alkaline, the determination in No. 1 of the total bicar- 
bonate minus the excess alkalinity (figured to bicarbonate) will give the 
amount of alkalinity consumed by the mixed acids and from which figure 
they may be calculated. 

• In the official granular salts the proportion of tartaric and citric acids 
is about 3 to 2. 

(7) Determine caffein in a 1-gram sample. 

(8) If hexamethylenetetramine is present, determine ammonia in a 
5-gram sample and calculate to hexamethylenetetramine. Caution must 



654 ORGANIC SUBSTANCES 

be observed, too, in keeping sample dry and to add undiluted concentrated 
sulphuric acid. 

(9) Determine moisture in 1 gram by drying in vacuo over sulphuric 
acid. 

(10) Make a qualitative test for Hthium with spectroscope, and if 
advisable determine the quantity. 

Many commercial tartaric acids and tartrates contain small quantities 
of lead, and their wholesomeness has become a problem for the food chem- 
ist. We are not especially concerned with the feature, but it may happen 
that the purity of a sample with respect to lead will be a question of 
importance in our work. The small quantity present is usually determined 
by color comparison, which is not a very safe method unless the absence 
of other heavy metals has previously been ascertained. Hence, in cases of 
moment or doubt the analyst ought to run careful qualitative tests before 
he attempts to arrive at any conclusions as to the quantity present. 

HYDROXYTRICARBOXYLIC ACIDS 

This group is represented by Citric Acid 

COOH 

I 
CH 2 

I 
C(OH)COOH 

I 
CH 2 

I 
COOH. 

Citric acid is used to considerable extent in medicine, occurring in a 
variety of products exploited for refrigerant and laxative purposes. It 
is somewhat antiseptic and antiscorbutic, is employed in pruritis, diph- 
theria, post partum hemorrhage, gangrene, sore mouth, excessive sweat- 
ing, inflammation of the throat, and scurvy. Ammonium citrate is almost 
always present in preparations containing beef peptones, such as beef, 
iron and wine, and cod-liver oil wines. 

It is present in granular effervescent salts and lithia tablets, and in 
combination with magnesium. It is a constituent of anti-fat mixtures 
combined with sugar. 

Citric acid crystallizes with one molecule of water. When heated -it 
dissolves in its water of crystallization and at 75° the water begins to 
evaporate. It becomes anhydrous at 135° and melts between that temper- 
ature and 152° C. Citric acid is efflorescent in warm air and deliquescent 
in moist air. Its presence in a sample is soon manifested if it is left exposed 



ORGANIC ACIDS 655 

in a laboratory. It dissolves in the water it attracts, and if sugar is present 
forms a sticky unsightly mass which is difficult to dry. 

At a high temperature it gives aconitic acid, and on further heating 
itaconic and citraconic. When slowly ignited it is gradually decomposed 
without the odor of burnt sugar and it dissolves in hot sulphuric acid 
with a brownish-yellow color, instead of the charring phenomenon 
characteristic of tartaric acid. 

It is readily soluble in alcohol and water, slightly in ether, and prac- 
tically insoluble in chloroform, benzol, and petroleum ether. 

It gives no precipitate with potassium chloride or acetate. Calcium 
hydroxide in excess gives a precipitate on boiling, which redissolves on 
cooling. When this test is performed, a little calcium may be precipitated 
by the carbon dioxide in the air, and when the solution is cooled the pre- 
cipitate will not entirely dissolve. Calcium citrate is insoluble in potassium 
hydroxide, but soluble in ammonium chloride and acetic acid. Neutral 
citrates are precipitated by calcium chloride on boiling, but free citric 
acid gives no precipitate. 

It does not reduce alkaline permanganate nor ammoniacal silver oxide. 

Citric acid in solution prevents the precipitation by alkalies of iron 
and zinc. 

It dissolves iron oxide, and on evaporating the liquid it will remain 
clear and finally scale when dry; tartaric acid dissolves the oxide, but 
on evaporating a precipitate occurs. 

Fusion with potash gives acetate and oxalate. When heated with 
hydriodic acid it is converted to tricarballylic acid, 

COOH • CH = (CH 2 COOH) 2 . 

Detection of Citric Acid. — Citric acid can be precipitated from its 
solution by lead acetate and the precipitate washed and decomposed by 
hydrogen sulphide exactly as described under the Detection of Tartaric 
Acid. The solution of ammonium citrate should then be tested with cal- 
cium chloride, calcium hydrate, and the other reagents noted in the table 
on page 651. 

L. Gowing-Scopes J proposes the following method, which he states 
is accurate in the presence of tartaric, succinic, oxalic, benzoic, and phos- 
phoric acids, but when malic, lactic, or salicylic acids are present the 
results are too high. The sample containing not over .04 gram of citric 
acid is exactly neutralized with N/10 alkali, using phenolphthalein, 
treated with 10 mils of a reagent (consisting of 68 mils cone, nitric acid, 
51 grams mercuric nitrate, 51 grams manganese nitrate; 100 mils water, 
finally made up to 250 mils and filtered) diluted to 200 mils and heated 
three hours with a reflux. The precipitate is washed by decantation, 

1 Analyst, 1913, 38, 12. 



656 



ORGANIC SUBSTANCES 



collected in a tared Gooch, and dried at 100° for five hours, one-sixth 
of the weight of the precipitate gives the amount of citric acid. The 
residue should be cream colored, any yellowish coloration indicating the 
formation of basic salts, which will cause too high results. 



Citric Acid in citrates and lemon juice * 

The method consists in decomposing the citric acid (first separated 
as calcium citrate) by gently warming with concentrated sulphuric acid 
and measuring the evolved carbon monoxide, 1 molecule of which is 
obtained from each molecule of citric acid. The apparatus used is shown 
in the accompanying figures. The upper part A is fitted to the flask B 



f=£? 





(150-mil capacity) by a ground joint, and the tubes D and Eand G and E 
may be connected respectively through the tap R, as also may the flask 
and the exterior. Two grams of the calcium citrate, moistened with water, 
are introduced into B, and the air in the flask is completely displaced by 
carbon dioxide, the absence of air being ascertained by means of an auxil- 
iary nitrometer, filled with potassium hydroxide solution (1:5) and 
attached to the T-piece; 25 mils of concentrated sulphuric acid are then 
run into B from A, and a slow current of carbon dioxide is again passed 
into the flask, which is warmed to 80-100° C. and occasionally shaken, 
the carbon monoxide evolved being collected in a nitrometer of 200 mils 
capacity, of which the lower part B 1 (100 mils capacity) is graduated in 
fifths of a mil. When the volume of gas becomes constant, the nitrom- 
eter is allowed to stand for half an hour and then, after washing the gas 
with potassium hydroxide solution, introduced through J, the volume 
is read, and the usual corrections are made for temperature and press- 
1 M. Spica., Chem. Zeit., 1910; 34, 1141. 



ORGANIC ACIDS 657 

ure. One mil of carbon monoxide, at 0° C. and 760 mm. indicates 
.009407 gram of citric acid (C6H6O7, H2O). The same apparatus may be 
used for the determination of carbonate in a citrate, by decomposing 
with a known volume of concentrated hydrochloric acid and measuring 
the evolved carbon dioxide over water. 



Citarin 

Sodium anhydromethylene citrate is the normal sodium salt of 
anhydromethylene-citric acid. 

CH 2 COONa 

| yCH 2x 
CO< >0 

I X CO / 
CH 2 COONa 

Citarin 

Anhydromethylene-citric acid is obtained by reacting on citric acid with 
paraformaldehyde, or with chlormethyl alcohol, CH 2 C10H. 

It is a white, granular, somewhat hygroscopic powder, having a faintly 
saline and aciduous taste, and a slightly acid reaction. It is readily soluble 
in about 1.5 parts of water, but insoluble in alcohol. Its solution splits 
off formaldehyde when heated, particularly in the presence of alkalies, 
and mineral acids separate from its concentrated solutions methylene- 
citric acid. It is incompatible with acid and alkalies and is decomposed 
by heat. It is claimed to be useful for gout and chronic rheumatism. 

Aconitic Acid 

COOH 

I 
CH 2 

I 
CCOOH 

II 
CH 

I 
COOH 

This acid is produced on heating citric acid to a high temperature. It 
occurs naturally in aconite tubers, larkspur, black hellebore, yarrow, 
Equisetum, and probably other plants. 



CHAPTER XVIII 

ORGANIC ACIDS— AROMATIC SERIES 

CARBOXYLIC ACIDS 

The aromatic carboxylic acids may be considered as derived from the 
hydrocarbons of that series by the substitution of one or more carboxyl 
groups for a corresponding number of hydrogen atoms. Two classes of 
compounds may be obtained, depending on whether the substitution is 
in the nucleus or in the side chain. Thus we may have toluic acid, 

/CH3 
CeH4<r 

X COOH 

or phenylacetic acid, C6H5CH2COOH, both from toluene. 

These acids may be obtained by oxidizing alcohols or aldehydes, by 
the hydrolysis of nitriles by alkalies or mineral acids, or by oxidizing the 
homologues of benzene with dilute nitric or chromic acid. In the latter 
case only acids which contain the carboxyl group united to the nucleus 
can be obtained, because the side chain is always oxidized to carboxyl, 
no matter how many CH2 groups are present. 

The aromatic acids are crystalline and may be distilled with steam 
without change. They are soluble in ether and alcohol and some of them 
fairly readily in petroleum ether, sparingly in cold water, but to a much 
greater degree in warm water. In all reactions affecting the carboxyl 
group they are analogous to the aliphatic acids, and give corresponding 
derivatives. Benzoic acid gives sodium benzoate, CeHsCOONa, ethyl 
benzoate, C6H5COOC2H5, benzoyl chloride, C6H5COCI, benzamide, 
C 6 H 5 COONH 2 , benzoic anhydride, (C 6 H 5 CO) 2 0. 

When distilled with calcium oxide they are decomposed with the forma- 
tion of the corresponding hydrocarbons. 

Two of the acids of this group, benzoic and cinnamic, are very important 
in medicinal chemistry. They occur both in the free state and in com- 
bination in the aromatic balsams of Peru and Tolu, and their salts are 
employed to a considerable extent. These two acids with salicylic ana 
its many derivatives, gallic and tannic acids, which are members of the 

658 



ORGANIC ACIDS— AROMATIC SERIES 659 

hydroxycarboxylic group, and phenolsulphonic acid and its derivatives, 
are the principal acids of the aromatic series of medicinal importance. 

BENZOIC ACID, C 6 H 5 COOH 

Benzoic acid is obtained from several sources, benzoin, toluol, naph- 
thalene, and urine. It is, of course, the same individual no matter what 
its source, though practitioners often ascribe different properties, depending 
on its origin. If a difference actually occurs it is probably due to the effect 
or absence of impurities in an article of ordinary commercial purity. 

Benzoic acid is a stimulant expectorant, and is an ingredient of bron- 
chitis mixtures. It is used for uric acid gravel, cystitis, acute gonorrhorea, 
and nocturnal incontinence. Its antiseptic value is well known and it 
takes part in the formulas of many mouth washes and douches for the 
nose and throat. Sodium benzoate is used in gout and rheumatism. 
Lithium benzoate often occurs in lithia tablets. 

Benzoic acid is used in surgeon's gauze. It is one of the ingredients 
of liquid camphor compound with opium, camphor, and oil of anise. In 
Brown's mixture it occurs with licorice, oil anise, powdered opium, cam- 
phor, and tartar emetic, with and without ammonium chloride. Cystitis 
tablets are composed of benzoic acid, borax, buchu, triticum, corn silk, 
Hydrangea and atropin sulphate. Mentholated throat tablets contain 
benzoic acid, menthol, anise, cocain, and eucalyptol. 

Sodium benzoate is an ingredient of nasal tablets and liquid nasal 
douches with bicarbonate, chloride, biborate, salicylate of sodium, thy- 
mol, menthol, oils of eucalyptus and gaultheria. It also occurs in tooth 
pastes. It is combined with caffein in hypodermic tablets. 

The acid prepared from benzoin usually carries the suggestion of the 
characteristic odor of the drug and may be slightly darker in color than 
the artificial acid. These characteristics, however, do not necessarily 
determine its origin, for it is possible to impart the same properties by 
subliming benzoic acid in presence of a little gum or by adding a small 
quantity of vanillin. Artificial benzoic acid may contain chlorinated 
products, traces of hydrochloric, sulphuric, or hippuric acid. 

Benzoic acid occurs in iridescent needle-shaped crystals, or in fine 
needles, melting 120-121°, soluble in most organic solutions, in hot water 
and slightly in cold water. It sublimes at the temperature of the water- 
bath and by this may be readily purified, and crystals obtained which give 
a sharp melting-point. Its vapor has a characteristic odor and an irritating 
action on the throat, producing violent coughing. 

Benzoic acid gives a flesh-colored precipitate with ferric chloride, and 
the reaction is best obtained by dissolving the acid in a little dilute ammonia 
and evaporating off the excess of gas. On dissolving the residue in water 
and adding the reagent a copious precipitate is thrown down. 



660 ORGANIC SUBSTANCES 

It gives no precipitate with bromine water, which distinguishes it 
sharply from salicylic acid. This property furnishes a ready and simple 
method of separating the two acids when they occur together. 

It does not give the odor of benzaldehyde when warmed with perman- 
ganate, being distinguished in this respect from cinnamic acid. The latter 
acid is furthermore unsublimable at the temperature of the water-bath 
under ordinary conditions. 

Benzcic acid yields benzene when distilled with excess of lime. When 
its vapors are passed over heated zinc dust benzaldehyde is formed. On 
distilling with phosphorus pentachloride, benzoyl chloride, C6H5COCI, 
is formed. The anhydride results when benzoyl chloride is treated with 
sodium benzoate. Both the anhydride and benzoyl chloride react with 
bodies containing an hydroxyl group giving benzoyl derivatives. 

Ethereal salts of benzoic acid are obtained by dissolving the acid in 
the appropriate alcohol, saturating with hydrochloride acid gas, and after 
standing for some time, pouring the mixture into water when the ethereal 
salt separates. Ethyl benzoate has a pleasant aromatic odor, and its 
formation under appropriate conditions furnishes one of the conclusive 
tests for cocain. 

Benzamide, C6H5COONH2, may be obtained by treating ethyl ben- 
zoate with ammonia. 

Benzonitrile, C6H5CN, is obtained by dehydrating benzamide or by 
treating diazo-benzene chloride with potassium cyanide and copper sul- 
phate according to Sandmeyer's reaction. 



C 6 H 5 N 2 C1+KCN = C 6 H 5 CN+KC1+N 2 



Meta-brom benzoic acid, melting 155°, is obtained when benzoic acid 
is heated with bromin and water to 125°. The ortho and para acids, 
melting 148 and 237° respectively, are obtained by oxidizing the cor- 
responding bromtoluenes with nitric acid. The nitro benzoic acids are 
produced in a similar manner. The nitro acids on reduction with nascent 
hydrogen yield the corresponding amido benzoic acids, C6Hs(NH2)COOH, 
which form salts with both acids and alkalies. 

The amido acids are of special interest, as they are the parent sub- 
stances of a class of esters used as anesthetics. Propaesin and anesthesin 
are the propyl ester and ethyl ester of the para acid. The ortho acid 
melts 144-145°, the para 186-187° and the meta 173-174° C. 

Beta-naphthol benzoate, benzoyl salicylic methyl ester, guaiacol ben- 
zoate, eugenol benzoate, hydrocotoin, will be described at length under 
Ethereal Salts. Benzoylphenylhydrazine and benzoylanilide will be men- 
tioned under Nitrogen Compounds and Amines. Benzoyl acetyl peroxide 
is described under Peroxides. 



!s. 



ORGANIC ACIDS— AROMATIC SERIES 661 

Benzoic acid is converted into meta-sulphobenzoic acid when heated 
with sulphuric acid, and small quantities of para are produced at the same 
time. The ortho acid is obtained by oxidizing toluene orthosulphonic 
acid, it gives an imide known as saccharin when heated with ammonia. 

/S0 2 OH /S0 2x 

C 6 H4< +NH 3 = C 6 H4< >NH+2H 2 

x COOH x CO / 

The sulpho acids yield hydroxy acids when fused with potash. 

Mohler's x test for benzoic acid, modified by von der Heide, 2 has been 
used extensively at the Bureau of Chemistry in testing food products. 
The suspected residue is dissolved in 1-3 mils of N/3 sodium hydroxide 
and evaporated until all the water is driven off. To the residue 5 to 10 
drops of concentrated sulphuric acid and a small crystal of potassium 
nitrate are added, and the mixture heated ten minutes in a glycerol bath 
at 120-130°, or for twenty minutes in a boiling water-bath. 

Meta-di-nitro benzoic acid is formed and the mixture is cooled, 1 mil 
water added and an excess of ammonia and boiled to break up any ammo- 
nium nitrite which may have been formed. After cooling, the solution, 
which should be in a test-tube, is treated with a drop of freshly prepared 
colorless ammonium sulphide without allowing the layers to mix, and the 
appearance of a red-brown ring indicates benzoic acid; on mixing, the 
color diffuses through the whole liquid, and on heating changes to greenish 
yellow, owing to the decomposition of the amido acid. Both cinnamic 
and salicylic acids yield amido acids, which give a red-brown ring, but the 
color is not destroyed on subsequent boiling. Phenolphthalein interferes 
with the test. 

Jonescu 3 recommends a simple test in which the suspected residue 
is dissolved in water slightly acidified with acetic acid, and ferric chloride 
and a few drops of hydrogen peroxide added. The liquid assumes a yellow 
tint, which gradually becomes violet owing to the conversion of benzoic 
acid to salicylic. 

Modified Jonescu Reaction. — One to 5 mg. of the acid in aqueous solu- 
tion are treated with 3 drops of ferric chloride (26 per cent (anhydrous 
basis) diluted 1-10), 3 drops hydrogen peroxide 1-10, and 3 drops ferrous 
sulphate 3 per cent, shaking after each addition. In about thirty seconds 
the reaction commences and the violet coloration attains its maximum 
in five to ten minutes. 

In the general scheme of analysis of medicinal preparations, benzoic 

1 Bui. Soc. Chim., 1890, 3 (3), 414. 
2 Zts. Nahr. Genussm., 1910, 19 (3), 137. 
3 J. Pharm. Chem., 1099 (4), 29, 523. 



662 ORGANIC SUBSTANCES 

acid will appear on shaking out the acid solution with petroleum ether. 
If none comes out at this point, but on shaking out subsequently with 
ether an impure residue is obtained which on testing apparently contains 
benzoic acid, it is evident that a small quantity only is present in the prod- 
uct. The residue left on evaporating petroleum ether is always purer 
than that obtained with ether, for this latter solvent has a solvent action 
on a wider range of substances. 

The crystalline residue should be examined first by allowing it to 
remain on top of the water-bath, but not over the direct steam, and observ- 
ing any sublimate which may collect on a watch-glass placed over the 
top of the receptacle. Benzoic acid soon collects in beautiful iridescent 
stalactites which can be easily scraped off and their melting-point deter- 
mined. The sublimate should also be subjected to Mohler's reaction and 
another portion dissolved in dilute ammonia, evaporated, and a solution 
of the residue treated with a drop of ferric chloride. 

Salicylic acid sublimes more slowly than benzoic and collects in quantity 
on the sides of the flask. Acetanilid also sublimes and might be mistaken 
for benzoic acid, but it is readily detected by the carbylamine reaction. 
Cinnamic acid does not sublime under these conditions. If salicylic acid 
or acetanilid occur simultaneously with benzoic acid, they should be 
separated before making the chemical test. The residue may be dissolved 
in water with a little acetic acid and precipitated with bromin water. 
On filtering, the benzoic acid will be in the filtrate, and after destroying 
the excess of bromin it can be shaken out and tested. 

Before attempting to determine the quantity of benzoic acid in a drug 
product, it is absolutely necessary to identify the other ingredients, and 
if other acids are present, their influence on the method must be taken 
into consideration, and appropriate procedures for their elimination con- 
ducted. 

If the sample is a tablet it should be thoroughly extracted with alcohol 
and the solvent evaporated in the presence of a slight excess of alkali. 
If the sample is a liquid the alcohol should be evaporated under similar 
conditions. The residue is then diluted with water, transferred to a 
separator and slight excess of hydrochloric acid added. It is then shaken 
with four successive portions of chloroform, using 70, 50, 40, and 30 mils, 
the combined solvents washed with water or saturated sodium chloride, 
the chloroform partly recovered by distillation and the balance evaporated 
to dryness in a beaker at room temperature, using a blast of dry air to 
hasten the evaporation. The residue of benzoic acid is dissolved in neutral 
alcohol, about one-fourth the volume of water added, and titrated with 
N/10 sodium hydroxide, using phenolphthalein as indicator. One mil 
N/10 alkali = .01217 benzoic acid. 

Salicylic acid if present can be separated and determined at the same 



ORGANIC ACIDS— AROMATIC SERIES 663 

time by dissolving the chloroform residue in warm water acidulating with 
acetic acid, cooling, and precipitating the salicylic acid with excess of 
bromin water, filtering and weighing the tribromphenol bromide as 
described under salicylic acid, and then shaking out the benzoic acid from 
the filtrate exactly as described above. 

If phenolic substances are present the residue must be dissolved 
in chloroform and shaken out three times with 10 per cent sodium bicar- 
bonate, which will remove the acids, and the alkaline solution acidified 
and again shaken out with chloroform. 

Cinnamic acid can be determined in presence of benzoic by treating 
a solution faintly acid with sulphuric acid with excess of standard bromin 
in potassium bromin, and after allowing the mixture to stand tightly 
corked, agitating occasionally, potassium iodide is added and the liber- 
ated iodin titrated with thiosulphate. The dilution of the cinnamic 
acid should be about 1-200. This method permits the simultaneous 
determination of both acids. The titration or gravimetric figure for the 
two is obtained, and then the solution in alkali is acidulated and the cin- 
namic acid determined. Garsed 1 described this method in his work on the 
Assay of Crude Cocain. 

There are a number of proprietaiy products containing small amounts 
of aromatic balsams the presence of which can be ascertained by detecting 
the acids. If the sample is evaporated until all the water is driven off 
and then extracted with alcohol, the balsams will dissolve, and on con- 
centrating and adding a little potash and boiling, the ester will be saponi- 
fied and on evaporating the alcohol, dissolving in water, acidifying with 
hydrochloric acid and shaking with ether or chloroform, the benzoic or 
cinnamic acid or both will go into solution, and on carefully evaporating 
the solvent they will be left in the residue and can be identified. 

HIPPURIC ACID. BENZOYL AMINO ACETIC ACID, C 6 H 5 CONHCH 2 COOH 

Hippuric acid occurs in the urine of herbivorous animals, from which 
it may be obtained in crystals, melting 187.5°. It decomposes at a higher 
temperature, giving a sublimate of benzoic acid and an odor suggestive 
of hay, followed by one characteristic of hydrocyanic acid. It is difficultly 
soluble in ether and cold water, more readily in hot water, and easily in 
alcohol and ethyl acetate. Calcium hippurate is used in cystitis, lithiasis, 
difficult dentition, and uric-acid diathesis. 

Methylene Hippuric Acid — Hippol 

This substance, about which there seeems to be some ambiguity as 
to its formula, is used as an urinary antiseptic. It melts 151°, and is 
soluble in alcohol, chloroform, ethyl acetate, and slightly in water. 

1 Pharm. J., 1903, 784. 



664 ORGANIC SUBSTANCES 



SACCHARIN 



yS0 2 v 

c 6 hZ )>nh 

Saccharin is sold under a variety of names, including garantose, gluside, 
glycophenol, glycosine, saccharinol, saccharinose, saccharol, saxin, sykose, 
zucherin, glusimide, agucirina, toluolsuss, neo-saceharin, etc. 

It is prescribed in cystitis and for sweetening foods and preparations 
used in diabetes and for obesity; to cover the bitter taste in certain prod- 
ucts, and as a general sweetener in pharmaceuticals. It is usually sold 
in tablet form with or without sodium bicarbonate. It is a common 
sweetener used in tooth pastes. 

It is a white or yellowish, odorless, microcrystalline powder, melting 
220°, somewhat soluble in water, and completely soluble in alkaline solu- 
tions from which it is precipitated on the addition of mineral acid if the 
solution is concentrated. It dissolves readily in alcohol and ether, but 
is practically insoluble in petroleum ether, chloroform, and benzol. 

It is best known on account of its intense sweet taste, which is apparent 
at considerable dilution. In order to compare its sweetening power with 
that of other substances, equal amounts should be dissolved in water con- 
taining, if necessary, sufficient bicarbonate to effect solution, and then 
each solution diluted until no sweet taste is apparent, the difference in 
dilution being a measure of the comparative sweetness. 

As it appears in analysis, saccharin is usually an amorphous residue 
which is left on evaporating the ether shake-out from an acid solution. 
It will be indicated on removing a small quantity on the end of the finger 
and touching it to the end of the tongue. Its presence should be further 
substantiated by dissolving the residue in ether and shaking out with dilute 
sodium hydroxide, which will remove the saccharin, but will leave any 
dulcin or other sweetener in the ether. The alkaline solution is trans- 
ferred to a test-tube, immersed in an oil-bath, the water evaporated and 
the temperature raised to 250° and held at that point for about twenty 
minutes. The alkaline mass is then dissolved in water, acidulated and 
shaken with ether, and the residue left on evaporation tested for salicylic 
acid, which results on fusing saccharin. The absence of salicylic acid in 
the original material must be assured by previously testing a portion with 
dilute ferric chloride. If salicylic acid is found, it can be separated by 
dissolving the residue in warm dilute hydrochloric acid, cooling, precipi- 
tating the acid with bromin water, filtering and boiling the nitrate to 
expel the excess of bromin, then adding a piece of sodium hydroxide and 
proceeding with the alkaline fusion as described above. 



ORGANIC ACIDS— AROMATIC SERIES 665 

Dulcin is an entirely different chemical substance and may be con- 
sidered either as a derivative of urea or phenetidin: 

/NH 2 /OC2H5 

C^O or C 6 H4< 

\NHC6H4OC2H5 x NHCONH 2 

It is also used as an artificial sweetener, but is not as intense in its power 
as saccharin. 

Licorice root contains a sweet substance, glycyrrhizinic acid, and 
Eupatorium rebaudianum also contains a sweet principle. 

Saccharin can be readily determined when it occurs by itself or with 
bicarbonate, by dissolving the tablet in water, and precipitating with 
hydrochloric acid and shaking out with ether. On filtering and evapor- 
ating the ether the saccharin will be left as a weighable residue. 

It can be separated from salicylic acid by means of bromin water, 
after the manner described for separating that substance from benzoic 
acid, and then shaken out with ether and weighed. 

When it occurs in mixtures with other substances soluble in chloro- 
form these may be dissolved out by the chloroform and the saccharin 
subsequently shaken out with ether. This method applies to products 
of the headache remedy type containing caffein, acetanilid, or acetphene- 
tidin, all of which are removed from an acid solution by shaking out with 
chloroform. 

Soluble saccharin is prepared by treating saccharin with sufficient 
aqueous ammonium carbonate to render it soluble and evaporating the 
solution to dryness. 

PHTHALIC ACIDS 

These are dibasic acids, and the ortho acid is the most important. 
Ortho phthalic or benzene-o-dicarboxylic acid, 

|COOH 

COOH 

is a colorless crystalline substance, melting at 184° with formation of the 
anhydride, this being the only phthalic acid capable of forming an anhy- 
dride. If the melting-point of the new substance is taken it will be found 
to be 128°. The acid is soluble in water, alcohol, and ether, and forms 
well-defined metallic salts and esters. 

When heated with resorcinol and a drop of sulphuric acid, fluorescein 
is produced, and the reddish-brown product when dissolved in dilute alkali 
and poured into water gives a yellowish-green fluorescent solution. This 



666 ORGANIC SUBSTANCES 

reaction is given by all the ortho dicarboxylic acids of the benzene series, 
but not the meta and para acids. 

Phthalyl chloride, boiling 275°, is obtained on heating the anhydride 
with phosphorus pentachloride. 

The anhydride sublimes readily in long needles, melting 128° and 
boiling 284°. It dissolves readily in alkalies, yielding salts of phthalic 
acid. On fusion with phenol in presence of zinc chloride it yields phenol- 
phthalein. 

Isophthalic acid is the meta form. It melts above 300° and when 
strongly heated sublimes unchanged. It is very sparingly soluble in water. 
Methyl isophthalate, CeEUCCOOCHs^, melts at 65°. 

Terephthalic acid, the para form, sublimes without melting. The 
methyl ester melts 140°. 

To prepare the methyl esters for identification the acid is warmed 
with phosphorus pentachloride and the clear solution poured into an 
excess of methyl alcohol. When the vigorous reaction has subsided, 
the liquid is poured into water, the separated salt collected, recrystallized, 
dried on a porous plate and then in vacuo. 

PHENOLPHTHALEIN 
J>C(C 6 H 4 OH) 2 

This substance, which is a derivative of phthalophenone, is prepared by 
heating 3 parts of phthalic anhydride with 4 parts phenol and 5 parts 
powdered zinc chloride at 1 15-120° for eight hours. The product is washed 
with water, dissolved in sodium hydroxide, filtered, and phenolphthalein 
precipitated with acetic acid. 

It has attained considerable importance in medicine as a laxative and 
will be found alone and in combination. It occurs as a white or faintly 
yellow crystalline powder, melting at 250°, readily soluble in alcohol, 
ether, and alkalies, and slightly soluble in water. The alkaline solutions 
are deep pink, the acid colorless. It is removed from an acid solution 
by shaking with ether and will be indicated by shaking out a portion 
of the ether solution with ammonia. Some of the anthraquinone deriv- 
atives occurring in rhubarb, senna, cascara, and other laxative drugs will 
give a pink color under similar conditions, but these derivatives are yellow 
and the yellow color is imparted to the ether, while the phenolphthalein 
is colorless in ether. 

The anthraquinone derivatives dye wool a yellow color from an acid 
bath. The color is stripped b}^ dilute ammonia and will give a second 
dyeing. An alcoholic solution of these derivatives on evaporation with 






ORGANIC ACIDS— AROMATIC SERIES 667 

ferric chloride leaves a yellow residue; phenolpkthaiein under similar 
condition leaves a pinkish residue with odor of phenol, the color disappear- 
ing on cooling or in the presence of moisture. Phenolphthalein goes onto 
wool, but no color is imparted, if the treated wool is dropped into dilute 
ammonia the characteristic pink color will appear. 

The separation of phenolphthalein from the anthraquinone derivatives 
has been described in the chapter on the Anthraquinone Drugs. 

Several derivatives of phenolphthalein are used in medicine, among 
which are the dicinnamate, diisolverate, dibutyrate, salicylate, and car- 
bonate. Halogen derivatives are obtained by heating phenols with halo- 
genated phthalic acid in presence of dehydrating agents. The product 
obtained from phenol and tetrachlorphthalic and melts at 316°. 

Tetraiodophenolphthalein or Nosoohen" 

(C 6 H 2 l20H) 2 C< >CO 

This substance, also known as Iodophen, is a light-yellow, odorless, 
tasteless powder insoluble in water and acids, soluble in ether, chloroform, 
and alkaline solution, and melting with decomposition at about 225° C. 
It is used as an antiseptic, sometimes being substituted for iodoform. 

The sodium salt is sold under the name Antinosin, and is a blue powder. 
It is used in a weak solution for spraying the mouth, nose, and throat 
in diphtheria, and for other affections of the mucous membrane. 

The bismuth salt is called Eudoxin. It is a reddish-brown, tasteless 
powder, insoluble in water, used as an intestinal antiseptic, 



IODONE 

Iodone is prepared by treating a solution of phthalic-acid anhydride 
in acetic ether, with a solution of iodin and potassium iodide and crys- 
tallizing the product from suitable solvents. 

It occurs in the form of dark green prismatic crystals which melt with 
decomposition at 163° C. When freshly prepared it is odorless, but on 
standing, traces of iodin are liberated, giving it a faint odor of iodin. 
It is gradually decomposed into phthalic acid, iodin, and potassium 
iodide by water, in which the decomposition products dissolve until a 
saturated iodin potassium iodide solution results. Any excess of iodin 
remaining in contact with the supernatant liquid remains unchanged. 
Alcohol, chloroform, and ether decompose iodone, but more slowly than 
water. Iodone crystals are stable in dry air; exposed to damp air, they 
gradually liberate iodin. 



668 ORGANIC SUBSTANCES 

CINNAMIC ACID, C 6 H 5 CH = CHCOOH 

Cinnamic acid is one of the best known unsaturated acids of the aro- 
matic series and is of great importance in drug work. It occurs free and 
combined in the aromatic balsams of Peru and Tolu and in storax, and as 
an ester in the aloeresinotannol of Barbadoes aloes. It is prepared com- 
mercially from these sources, and also by heating benzaldehyde with 
acetic anhydride and anhydrous sodium acetate. This reaction is known 
as Perkin's reaction and is a general one for the preparation of unsaturated 
aromatic acids. 

C 6 H 5 CHO+CH 3 COOH = C 6 H 5 CH = CHCOOH+H 2 

Cinnamic acid is employed in the treatment of tuberculosis and lupus. 
It is used alone and in combination with arsenic and opium and with 
cocain. It will be found chiefly, however, in the aromatic balsams, which 
are used to a large extent, and its chemistry is, therefore, intimately con- 
nected with these drugs. 

Cinnamic acid is unsaturated. It crystallizes from water in needles 
melting 133-135°, boils 300-304°, soluble in alcohol, ether, chloroform, 
and petroleum ether. It distills with steam, but does not sublime at 
the temperature of the water-bath. It combines directly with bromine, 
yielding phenyl a/3-dibrom propionic acid, CeHsCHBrCHBrCOOH. On 
reduction with sodium amalgam it is converted into phenylpropionie 
acid, melting 48-49°. When distilled with lime it is decomposed into 
carbon dioxide and phenyl ethylene or styrolene. 

C 6 H 5 CH = CHCOOH = C 6 H 5 CH = CH 2 +C0 2 

Concentrated nitric acid converts it into a mixture of ortho and para- 
nitrocinnamic acids. The para acid is readily separated from the ortho 
and identified by its melting-point. 

Cinnamic acid when warmed with permanganate is converted in part 
to benzaldehyde, which is recognizable by its odor. 

It may be further identified by the formation of the para nitro com- 
pound. 

Stir .1 gram of the acid into 3 mils fuming nitric acid. It will dis- 
solve at first, but a precipitate soon appears. Add 30 mils of cold water, 
stir, filter, and wash with 10 mils cold water. Transfer the precipitate 
to a test-tube and boil with 5 mils alcohol, cool, shake, filter and wash 
with 5 mils cold alcohol. Boil the precipitate with 5 mils ether, cool, 
shake, filter and wash with 5 mils cold ether, dry precipitate at 100° and 
determine the melting-point of the paranitrocinnamic acid, which softens 



ORGANIC ACIDS— AROMATIC SERIES 669 

at 270° and melts at 286-287°. Any orthonitro acid or nitrobenzoic acid 
formed will be removed by the alcohol and ether. 

It has been claimed that cinnamic acid prepared from Storax differs 
slightly from the synthetic acid in melting-point, and in the character 
of its crystalline form, but it is probable that any difference is due to small 
quantities of impurities. 

Cinnamic acid can be titrated directly by alkali by dissolving it in 
neutral alcohol, using phenolphthalein. 

When it is the only ether soluble acid present in a mixture, it can be 
determined by dissolving the sample in water, acidifying with dilute sul- 
phuric acid and shaking out with ether. The ether is washed, filtered, 
and evaporated at a low temperature or spontaneously and the acid titrated 
as above. 

In the case of products which do not dissolve in water, but which may 
be soluble in ether, the sample is treated with the solvent, filtered if 
necessary and the ether solution shaken several times with 10 per cent 
sodium bicarbonate. The alkaline liquid is then acidulated with sulphuric 
acid and the cinnamic acid shaken out with ether and determined. 

When the cinnamic acid occurs in esters, resort must be had to saponi- 
fication. Usually a certain amount of free acid is present at the same 
time and if desired, both the free and combined acid can be separately 
determined in one sample. The product is treated with ether and the solu- 
tion filtered into a separator and shaken out with bicarbonate to remove 
the free acid which is determined as above described. The ether solution 
is then treated with excess of alcoholic potash and boiled under a reflux 
condenser. The alcohol is finally evaporated and the residue dissolved 
in water, filtered into a separator, the cinnamic acid set free from the potas- 
sium salt with sulphuric acid, shaken out with ether and finally titrated. 

Sodium metaoxycyanocinnamate Zimpher 
C 6 Hi(OH)CH = CCNCOONa 

This a yellowish-white crystalline substance soluble in water and dilute 
alcohol. It is used in dyspepsia and in gastro-intestinal atony. 

TRUXILLIC ACID 

Truxillic acid, which is a dicinnamic acid, has been described at length 
under the Coca Alkaloids. 

Atropic Acid, CH 2 = C.C 6 H 5 — COOK. 

Atropic acid is obtained on boiling tropic acid for a long time with 
barium hydroxide. It melts 106-107°, is volatile with steam and soluble 
in alcohol, ether and slightly. in water. 

Isatropic Acids, a and 0. 



670 ORGANIC SUBSTANCES 

These acids result on heating atropic acid. The a acid is 
C6H5CCOOHCH2C6H4CHCOOHCH2. 



It melts 237-238°. The /3-acid melts 206°. 

Tropic Acid, C 6 H 5 CH(CH 2 OH)COOH. 

Tropic acid is one of the hydrolytic products of atropin. It melts 
117-118° and is soluble in alcohol, ether and hot water. 

HYDROXY CARBOXYLIC ACIDS 

There are two classes of these acids according as the OH group is in 
the nucleus or the side chain. In the first case they have phenolic charac- 
teristics, and such acids are both phenols and acids. In the second case 
they have alcoholic characteristics, and compounds of this class, such 
as mandelic acid, C6H5CHOHCOOH, have properties closely resembling 
those of the fatty hydroxy acids. 

The first class contains two acids, which are of especial importance 
in drug work, salicylic and gallic. The hydroxy acids of this class may 
be prepared from the hydrocarbons by forming the nitro-compounds and 
then the amido compounds, which on treatment with nitrous acid gives the 
hydroxy acid. They also result when the aromatic acids are sulphonated 
and the sulphuric acids fused with potash, the meta compounds resulting 
by this methocL The ortho acids result generally when a sodium phenolic 
compound is heated to about 200° C. in a stream of carbon dioxide. Most 
dihydric and trihydric phenols may be converted into the corresponding 
hydroxy acids by heating them with ammonium carbonate or potassium 
bicarbonate. Another method consists in boiling a strongly alkaline 
solution of a phenol with carbon tetrachloride, the ortho acid resulting 
in greatest amount with varying proportions of the para. 

.COONa 
C 6 H 5 ONa+CCl4+5NaOH = C 6 H4< +4NaCl+3H 2 

X)H 

These acids are colorless crystalline solids more readily soluble in 
water and less volatile than the acids from which they are derived, and 
soluble in the ordinary organic solvents. When heated with lime they 
are decomposed with the formation of phenols and carbon dioxide. The 
ortho acids give color reactions with ferric chloride, but the m- and p-acids 
give no coloration. 

They form salts with carbonates and with the calculated quantity 
of caustic alkali, but when an excess of alkali is added the hydrogen of 
the OH group is displaced. The di-metallic salts are decomposed by 



ORGANIC ACIDS— AROMATIC SERIES 671 

carbon dioxide with the formation of mono-metallic salts, but the metal 
in the carboxyl group cannot be displaced by it in this way. They yield 
well-defined precipitates with bromin. 

The ethereal salts are prepared by saturating a solution of the acid 
in the proper alcohol with hydrogen chloride. By this treatment only the 
hydrogen of the carboxyl is displaced and normal salts such as methyl 
salicylate are produced. These compounds still have phenolic properties 
and dissolve in alkalies, forming metallic derivatives such as methyl 
potassium salicylate, which when heated with alkyl halogens yield alkyl 
derivatives such as methyl methyl salicylate, C6H4(OCH 3 )COOCH3. If 
dialkyl compounds of this type are hydrolyzed with alcoholic potash, 
only the alkyl of the carboxyl group is removed. The other alkyl group 
is not removed even on boiling with alkalies, but when heated with hydro- 
chloric acid it is converted into the hydroxy acid. 






OCH 3 /OH 



C 6 H4< +HI = C 6 H4< +CH3I - 

x COOH x COOH 



SALICYLIC ACID 

Salicylic acid occurs widely distributed in nature in the form of its 
methyl ester, and this compound forms the greater part of oil of winter- 
green or gaultheria and oil of sweet birch. It has been prepared commer- 
cially from these oils and the sodium salt of the acid from this source is 
still preferred by some practitioners instead of that from the synthetic 
acid. There may have been some reason for this preference in the early 
days of the synthetic acid, because of the presence of objectionable 
impurities, but in its present high state of purity it is probable that any 
supposed difference is due to prejudice, and not to any inherent difference 
in properties. 

Salicylic acid and the salicylates are extensively employed in remedies 
for rheumatism and gout and to some extent for colds and fever. It is 
also used in remedies intended for local application in veterinary practice 
and in corn remedies. Its use as a preservative and an anti-fermentative 
is well known. 

The acid is dispensed alone or in the form of its sodium salt in pills 
and tablets of different strengths, and combined with morphin sulphate. 
It is combined with sodium bicarbonate, colchicin, and guaiac in rheu- 
matism tablets; with sodium sulphate, Nux Vomica, ipecac, and Capsi- 
cum in anti-fermentative tablets; and with astringent drugs for leucorrhea. 
Elrxir of Salicylic acid compound contains also Cimicifuga, Gelsemium 
and potassium iodide and it will be found in cough mixtures containing 
eriodictyon, licorice, wild cherry, potassium bromide, Grindelia, and tar. 



672 ORGANIC SUBSTANCES 

Sodium salicylate is a component of many different tablet compounds. 
It will be found with acetanilid, acetphenetidin, codein, caffein, and sodium 
bicarbonate in remedies of the headache and cold type; also with Hyos- 
cyamus, camphor monobromated, acetanilid and Gelsemium for migraine ; 
in rheumatism mixture with colchicin, codein, and Digitalis; with aconite, 
belladonna, bryonia, morphin, mercuric iodide, and oil of gaultheria for 
follicular tonsillitis; with eucalyptol, thymol, and menthol and sodium 
benzoate, borate, bicarbonate, and chloride in nasal tablets; and with 
ginger, Capsicum, and cardamom in anti-fermentative mixtures. 

Sodium salicylate is used in liquid rheumatism remedies with the 
salicylates of potassium and Hthium and manaca, and also with colchicin. 

Bismuth salicylate is a basic salt used for intestinal catharrh, and will 
sometimes be encountered in tablet form alone, and with zinc sulpho- 
carbolate and aromatics. 

Salicylic or ortho hydroxybenzoic acid occurs in white needle-like 
crystals, melting 156°, subliming at the temperature of the water-bath 
and volatile in a current of steam. It is slightly soluble in cold water, 
readily on warming and dissolves in all the ordinary organic solvents. Its 
neutral solution gives an intense violet color with ferric chloride, it gives 
a precipitate of tribromphenol bromide with bromin water which on 
filtering, treating with sodium bisulphite and washing yields tribromphenol 
melting 92.5-93.5, and from a solution alkaline with soduim carbonate, 
a violet-red precipitate of tetraiodophenylenquinone, (CeEfe^O^, with 
iodin in potassium iodide. Silver nitrate and lead acetate give precipi- 
tates with neutral salicylates, but not with the free acid. Barium chloride 
does not give a precipitate. Fehling's solution is reduced by the acid. 

The para and meta hydroxybenzoic acids isomeric with salicylic have 
different melting-points and do not give the violet color with ferric chloride. 
The para melts 213-214° and the meta 200°. They are but sparingly solu- 
ble in chloroform. 

Alkaline solutions of salicylic acid give a precipitate of the acid when 
acidified with mineral acid, and on shaking with ether it is entirely dis- 
solved. It is partially removed from its acid solution by petroleum ether, 
but if the amount is large this solvent seems incapable of removing the 
entire quantity, even after several shake-outs. The first two or three 
shakings remove noticeable quantities, but after this the successive shak- 
ings seem to have little effect. 

Salicylic acid may be removed from an ether solution by shaking with 
sodium bicarbonate, differing in this respect from phenol and furnishing 
a means of separation. 

Para-creosotic acid is about the only acid which is likely to be found 
in salicylic acid, and its presence will be indicated by a lowering of the 
melting-point. 



ORGANIC ACIDS— AROMATIC SERIES 673 

If .25 gram of the acid is triturated with 5 mils of water and poured 
into a test-tube, treated with 2 drops of 2 per cent alcoholic solution of 
furfuraldehyde, shaken, and then 2 to 3 mils of concentrated sulphuric 
acid poured carefully to the bottom of the tube, a brown zone appears if 
o-creosotic is present, and a violet zone if phenol or m- and p-creosotic 
acids are present. 

One gram of salicylic acid dissolved in 5 mils water and 1 mil nitric 
acid 1.2 sp. gr. and boiled five minutes, forms nitro salicylic acid, which 
may be precipitated by pouring into 20 mils water and purified by recrys- 
tallization from hot water. The nitro acid sinters at 220 and melts at 
226°, and serves as a means of identification. 

Fuming nitric acid converts salicylic acid to picric acid. 

Salicylic acid dissolves in formaldehyde solution and on adding con- 
centrated sulphuric acid a precipitate is obtained, colorless at first, but 
becomes red and the solution magenta. 

A solution of salicylic acid or a salicylate treated with sodium nitrite, 
acetic acid, and a drop of copper sulphate and boiled gives a blood red 
color. Benzoic and cinnamic acid do not give this test. 

When carried out in the following manner Jorissen's test is stated 
to be considerably more delicate than the ferric chloride reaction. The 
solution to be tested is treated with 4 to 5 drops of 10 per cent solution 
of sodium or potassium nitrite, 4 to 5 drops of 50 per cent acetic acid, 
and 1 drop of a 1 per cent solution of copper sulphate, the liquid being 
shaken after the addition of each reagent. After heating in a boiling 
water-bath for forty-five minutes and cooling the color is examined against 
a white background, a blank test being carried out in a similar manner. 
In this way .005 to .01 mg. of salicylic acid in aqueous solution can be 
detected: faint but perceptible reactions are obtained with 5 to 8 mils 
of a 1 : 1,000,000 solution, and with 18 to 25 mils of a 1 : 3,500,000 solu- 
tion. The ferric chloride and Jorissen reactions may be applied to the 
same solution of salicylic acid, the liquid, after the addition of ferric 
chloride, being diluted until the violet color disappears and then sub- 
mitted to the Jorissen test. Benzoic, cinnamic, and tartaric acids, 
maltol, isomaltol, orcinol, arbutin, resorcinol, and phlorizin do not respond 
to the Jorissen test. A 1 : 100,000 solution of phenol gives the same 
color as a 1 : 1,000,000 solution of salicylic acid. With the Millon reagent 
phenol can be detected at a dilution of about 1 : 2,000,000. With sali- 
genin the limit of delicacy of the ferric chloride reaction is between 1 : 
10,000 and 1 : 20,000; in the Jorissen test saligenin gives a red color at 
1 : 10,000, a yellowish tint at 1 : 100,000, and no reaction at 1 : 1,000,000. 
2-hydroxyisophthalic acid gives the Jorissen reaction up to a dilution 
of 1 : 100,000, but is easily distinguished from salicylic acid by the color 



674 ORGANIC SUBSTANCES 

it gives with ferric chloride. Methyl-ethyl acetoacetate gives neither 
the Millon nor the Jorissen reaction at a dilution of 1 : 1000. 

The mono-metallic salts are prepared by neutralizing a hot aqueous 
solution with metallic carbonate and are as a rule soluble in water. The 
dimetallic salts are obtained by employing an excess of metallic hydroxide 
and, with the exception of the alkali salts, are insoluble. The dimetallic 
salts are decomposed by carbon dioxide with formation of the mono- 
metallic salts. 

In the general scheme of analysis salicylic acid appears first on shak- 
ing out the acid solution with petroleum ether, and will be indicated on 
testing the residue with ferric chloride. If benzoic acid is present it can 
be separated by precipitating the salicylic acid with bromin water and 
the identity of the tribromphenol established by washing, drying, and 
determining its melting-point. 

If the acid or its salt occurs alone in a product or in a mixture where 
it is the only substance removable from acid solution by ether, its deter- 
mination is simple. Tablets in sufficient quantity, usually 5 to 10, should 
be introduced into a separator, a little water added until they are dis- 
integrated, diluted, sulphuric added to render the solution distinctly acid 
and the salicylic acid extracted with ether, using three shakeouts. The 
combined ethereal solutions are then washed with water, filtered through 
a dry filter into a tared beaker, washing out separator and filters with more 
ether, and the solvent evaporated using a fan and then dried in a vacuum 
desiccator and weighed. 

Liquids should be acidified with sulphuric acid and the salicylic acid 
shaken out precisely as above. In some cases it is advisable to shake the 
acid back into an alkaline solution with dilute sodium hydroxide, and after 
collecting the alkali in another separator the salicylic acid is liberated by 
sulphuric acid, and shaking out with ether and determined as above. 

Salicylic acid can be titrated directly with alkali, using phenolphthalein 
1 mil N/10 alkali = .0138 gram acid. 

In cases where the acid occurs mixed with benzoic acid, the com- 
bined acids should be shaken out, dried in vacuum and weighed. The 
residue is then dissolved in about 2 to 5 mils alcohol, diluted with dilute 
hydrochloric acid, bromin water added in excess, the flask stoppered 
and allowed to stand until the tribromphenol bromide has settled and 
the liquid is clear. The mixture can then be filtered through a Gooch, 
the excess of bromin boiled off from the filtrate and the benzoic acid 
shaken out with chloroform and determined, or the tribromphenol bromide 
in the Gooch can be washed with sodium bisulphite solution followed by 
water, and then dried in vacuo and weighed as tribromphenol. 



ORGANIC ACIDS— AROMATIC SERIES 675 



DETERMINATION OF SALICYLIC ACID BY BROMIDE BROMATE METHOD 
DESCRIBED IN DETAIL IN THE NEW EDITION OF ALLEN 

The process is as follows: A known weight of the sample is dissolved 
in water (preferably with the aid of a little sodium hydroxide) and a 
volume corresponding to about .100 gram of salicylic acid diluted to 
about 100 mils with water in a stoppered bottle. Ten mils of hydro- 
chloric acid (sp. gr. 1.1) is next added (von Genersich states that it is 
preferable to add the salicylic acid solution to the bromate solution after 
the acidification of the latter), followed by a known volume (about 50 to 
60 mils) of a solution containing sodium bromate and bromide, of which 
sufficient should be used to give about 75 per cent of bromine in excess 
of that entering into the reaction. 1 The bottle is closely stoppered, well 
shaken, and allowed to remain in the dark for at least one hour to ensure 
the completion of the reaction. 2 Another bottle containing an equal 
quantity of the bromin solution is similarly diluted and acidified, and 
left to stand side by side with the sample. A solution of potassium iodide 
(10 per cent) is next added to the contents of both bottles, and the liberated 
iodine titrated with a decinormal solution of sodium thiosulphate (24.827 
grams of Na 2 S203+5H 2 per liter). Each 1 mil of this thiosulphate solu- 
tion required represents .008 gram of bromin in excess of that which 
has reacted with the salicylic acid, .138 gram of which cause the disappear- 
ance of .480 gram of free bromin, or as much as will be liberated by about 
50 mils of the bromin solution. The observation of the end-point may 
be assisted by the use of starch paste, but it is important that this should 
not be added until the liquid is nearly decolorized. Hence, if a prepa- 
ration already containing starch is to be examined, the salicylic acid must 
first be extracted by alcohol or other suitable solvent, and the process 
applied to the solution. In the case of wine and beer, the salicylic acid 
should be first extracted by the use of a mixture of ether and light petro- 
leum, and the process applied to the aqueous liquid obtained on shaking 
the above solution with sodium hydroxide. 

A. Seidell 3 has made an exhaustive study of the determination of sali- 
cylates by the bromin method of Freyer 4 which is essentially the Koppes- 

1 This solution is prepared by dissolving 19.5 grams of bromin ( = 6.5 mils) in about 
100 mils of water containing 10 grams of sodium hydroxide. The liquid thus obtained 
is boiled well, and then diluted with water to 2 liters. The solution keeps indefinitely. 
On addition of hydrochloric acid, the whole of the bromin present is liberated accord- 
in to the equation : 

5NaBr +NaBr0 3 +6HC1 = 6NaCl +3Br 2 +3H 2 

2 A more prolonged standing is desirable when very accurate results are required. 

3 J. Am. Chem. Soc, 1909, 1168; Am. Chem. Jour., 1912, 508. 
* Chem. Ztg., 1896, 20, 820. 



676 ORGANIC SUBSTANCES 

chaar method, and by the iodin method of Messinger and Vortmann x 
and concludes that the results obtained were not satisfactory or of uncer- 
tain reliability. At the time of his second investigation he was engaged 
in evolving a satisfactory method for determining thymol, and he finally 
accomplished his purpose and showed further that the method was applic- 
able for estimating salicylic acid. 

The details of the method as. finally elaborated are as follows: The 
weighed sample of .1 to .5 gram of thymol or salicylic is placed in a 300- 
mil glass-stoppered bottle with 1 to 2 mils carbon tetrachloride and 100 
mils water. Bromin vapor is then poured into the mixture until the 
color, after thorough shaking, shows that considerable excess of bromin 
is present. After one-half hour 5 mils of carbon bisulphide and immediate- 
ately thereafter 5 mils of aqueous 20 per cent potassium iodide solution 
are added and the liberated iodin corresponding to the free excess of 
bromin is titrated with .1/N thiosulphate; an additional amount of 
potassium iodide solution is added and if no further liberation of iodin 
occurs the reading on the burette is taken. Five mils of aqueous 2 per cent 
potassium iodate solution are then added and after thorough shaking the 
titration with thiosulphate is continued until the iodin color is just 
discharged for the second time. The completion of the reaction is tested 
by further addition of potassium iodide and iodate solutions. The dif- 
ference between the first (which should be from about 5 to 15 mils .1/N 
thiosulphate) and the second readings corresponds to the hydrobromic 
acid formed by the action of bromin on the thymol. The calculation 
is made on the basis of two molecules of hydrobromic acid per molecule of 
thymol; 1 mil .1/N thiosulphate is, therefore, equal to .0075056 gram 
thymol, or .006883 gram salicylic acid. 

W. O. Emery 2 has obtained excellent results by weighing the tetra- 
iodophenylenequinone obtained by precipitating a solution of salicylic 
acid in excess of sodium carbonate by iodin. This method may be 
employed in separating salicylic acid from cinnamic acid, and Emery 
gives in detail two procedures to be employed in working with liquid 
and solid headache mixtures, and these have been grouped with several 
others, in the chapter on acetanilid, acetphenetidin, etc. The details 
in so far as they apply to salicylic acid are as follows: The acid after 
separation from other substances by appropriate means, is manipulated 
into chloroform solution, and run into a 200-mil Erlenmeyer containing 
10 mils water and 1 gram dry sodium carbonate, sufficient to fix all the 
salicylic acid present, and distilled over a small flame until the chloroform 
has been expelled. The aqueous solution is transferred to a liter flask, 
treated with 10 grams of dry sodium carbonate, and made up to the mark, 

1 Ber. Chem. Ges., 1890, 23, 2753. 

2 U. S. Dept. Agri. Bu. Chem., Bull. 152, 1911, 236; Ibid., Bull. 162, 1912, 195. 



ORGANIC ACIDS— AROMATIC SERIES 677 

100-mil aliquots are transferred to 200-mil Erlenmeyers, heated nearly to 
boiling, 35 mils of N/5 iodine in potassium iodide added (or double this 
quantity of N/10 iodin) enough to ensure an excess of iodin. The mix- 
ture is heated on the steam-bath at nearly boiling temperature for one 
hour, during which time a violet-red precipitate of tetraiodophenyle- 
quinone (CeEfel^O^, will appear. The excess of iodin is removed by a 
few drops of sodium thiosulphate, and the liquid decanted through a tared 
Gooch, care being taken that most of the precipitate remains in the flask. 
The precipitate is treated with 50 mils boiling water, digested ten minutes, 
poured into the Gooch, and the balance of the precipitate washed out 
with hot water. It is then dried to constant weight at 100°. The weight 
of the substance multiplied by .4654 gives the amount of sodium salicylate. 

Sodium salicylate is the most important medicinal salt of salicylic 
acid. It should be readily and completely soluble in water, and on adding 
hydrochloric or sulphuric acid, the acid is precipitated and may be removed 
by ether. The acid can be determined by this method, or by the bromide- 
bromate or iodin methods. 

Some firms make a specialty of selling a product made from the acid 
obtained from oil of wintergreen. This is often called " Sodium Salicylate 
true " and other designations to distinguish it from the salt made with 
synthetic acid. There is no way of distinguishing between the two if 
they are both pure, but, if in separating the acid, it is found contaminated 
with cresotic acid it is evident that the synthetic product was used to make 
the salt. A negative test, however, signifies nothing. Some products 
have a suggestion of wintergreen odor, but this also is no proof that the 
salt was prepared from natural oil. 

Potassium and lithium salicylate have a limited use in medicine and 
basic bisumuth salicylate and basic mercury salicylate will be encountered. 
Didymium salicylate is called dymal. 

Alkaloidal salts of salicylic acid used commercially include antipyrin 
salicylate known as salipyrin, hexamethylenetetraamine salicylate, and 
phenocoll salicylate or salocoll. 



DERIVATIVES OF SALICYLIC ACID 

The ingenuity of the manufacturer of pharmaceuticals has resulted 
in the production of vast numbers of derivatives of salicylic acid. 

In this list which follows the derivatives have been divided with respect 
to the molecular change in the original acid. Those where the change 
affects the nucleus alone are placed together, those where the hydroxyl 
is esterified are assigned to another group, and so on. 

The first group consists really of substituted acids, and the chemical 



678 ORGANIC SUBSTANCES 

properties of these are in a general way similar to those of the parent 
substance. 

The second group consists of acids possessing a free carboxyl group, 
but with a substituted hydroxyl. These acids are removed from their 
solutions in ether by caustic alkalies and bicarbonates, but are very spar- 
ingly soluble in water, and the aqueous solution does not give any reaction 
with ferric chloride until it has been boiled and cooled. 

The third group is made up of alcoholic esters containing the free 
phenolic hydroxyl of the original acid. They are all removed from their 
ether solution by caustic alkalies, but are not taken out by bicarbonates. 
The aqueous solution gives colorations with ferric chloride in the cold. 
When saponified with alcoholic potash they yield sodium salicylate and 
an alcohol. If the alcohol is volatile it can be distilled off from the alka- 
line solution, mixed with the ethyl alcohol of the reagent, and then sep- 
arated and identified. 

The members of the fourth group, which includes esters with phenols 
instead of alcohols, resemble those of the third in their actions toward 
alkalies and bicarbonates. They are much less soluble in water, and on 
hydrolysis with alcoholic potash yield salicylic acid and a phenolic com- 
pound. The alkaline solution may be evaporated until the alcohol has 
been driven off and then the residue transferred to a separator, acidified, 
and shaken with ether, which will dissolve both the salicylic acid and the 
phenol; on separating the solvent and shaking it first with sodium bicar- 
bonate solution and then with sodium hydroxide, the acid will pass into 
the bicarbonate and the phenol into the alkali. The two alkaline solu- 
tions can then be acidified separately and the acid and phenol shaken 
out with ether and obtained in a condition for identification. 

The fifth group is relatively small and contains those substances in 
which both the hydroxyl and the carboxyl groups are esterified. They 
are of course indifferent to either caustic alkali or sodium bicarbonate 
when dissolved in ether, and are thus readily differentiated from any of 
the preceding substances. When hydrolyzed with alcoholic potash they 
yields acids, alcohols, and phenols depending on their composition, and 
which may be detected as described in the preceding paragraphs. 



ORGANIC ACIDS— AROMATIC SERIES 



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680 



ORGANIC SUBSTANCES 



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ORGANIC ACIDS— AROMATIC SERIES 



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ORGANIC SUBSTANCES 



OQ 



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Ortho not used medicinally. 
Meta and para used as sub- 
stitute for salol 




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Intestinal antiseptic, anti- 
rheumatic 




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ORGANIC ACIDS— AROMATIC SERIES 



683 



ESTERS INVOLVING BOTH OH GROUPS, AND THEIR DERIVATIONS 

/O(X) 
C 6 H 4 <( 

X COO(X!) 



Acetyl methyl 
salicylate. . . . 


/OCOCH3 
X COOCH 3 


Methyl Aspirin 
54° 


Insol. 


Sol. 


Sol. 


Antineuralgic 


Methyl benzoyl 
salicylate. . . . 


c 6 h/ 

x coo(c 6 h 3 co) 


Benzosalin 85° 




Sol. 




Intestinal anti- 
septic. 


Acetyl phenyl 
salicylate. . . . 


/OCOCHs 
X COOC 6 H 5 


Vesipyrine 
Acetyl Salol 
97° 


Insol. 


Sol. 






MISCELLANEOUS 



Salicyl-a- 

§ methyl 
phenyl-hy- 
drazone. . . 



Salicyl-quinin. 



C 6 H 8 CH»N • N • CH • CeH^OH 



C 6 H,OHCOOC2oHaN20 



Agathin 74 c 
Cosmin 



Saloquinine 130' 



Insol. 



Insol. 



Sol. 



Sol. 



Sol. 



Sol 



Antirheumatic, 
antineuralgic 



Antineuralgic, 
antiperiodic, 
analgesic, 
febrifuge 



Salicyl quinirt 
salicylate. . . 



Condensation 
product of 
salicylic and 
gallic acids. . 



C 6 H 4 OH, COOCOC 6 H 2 (OH).i 



Salitannol 210° 



SI. sol. 



Insol. 



Spar. 
Sol. 



Antineuralgic, 
antirheumatic 



Insol. 



Substitute for 
salol 



Condensation 
product of 
salicylic and 
boric acids. . 



(CcHiOCOOH) 2 BOH 



Borosalicylic 
acid 



Antiseptic 



Phenyl Salicylate 

C 6 H40HCOOC 6 H5 

Salol 

Salol is used as an intestinal antiseptic and occurs alone in tablets 
and in powders and mixed with bismuth subnitrate, subcarbonate and 
subgallate, calomel, sodium bicarbonate, zinc sulphocarbolate, and pepsin. 
It is employed in typhoid fever and in some forms of dyspepsia and 



684 ORGANIC SUBSTANCES 

bowel trouble, as chronic constipation. It is often dispensed with acet- 
anilid, acetphenetidin, lactophenin, and other anilides and phenetidins. 

It is a compound of many gonorrhea mixtures with sandalwood oil, 
copaiba, oleoresin of cubeb, and pepsin. 

It is sometimes used externally as an antiseptic for sores and wounds. 

Salol is a white crystalline powder with a faint phenolic odor, melting 
42-43° C, almost insoluble in water, soluble in alcohol, ether, chloroform, 
fixed and volatile oils. Its solution in alcohol gives a violet color when 
treated with dilute ferric chloride, but if a few drops of the alcohol solu- 
tion is added to 10 mils of dilute ferric chloride, a white cloudiness, but 
no color, will be produced on shaking. When warmed with sodium 
hydroxide it is hydrolyzed, and on diluting with water and acidulating, 
salicylic acid separates and the odor of phenol will be apparent. The 
two components can then be readily separated and identified. 

Salol can be removed from a solution of ether or chloroform by fixed 
alkali, and this property furnishes a ready means of separating it from 
acetphenetidin and other antypyretics with which it commonly occurs. 

In order to establish its identity in a mixture of oils, the sample is 
dissolved in ether, shaken with acid to remove basic constituents, and then 
extracted with potassium or sodium hydroxide, which will remove the 
salol. The latter can then be recovered by acidulating and shaking out 
with ether. If any fatty acids are removed at the same time they can 
usually be separated from the salol, by shaking the ether solution with 
sodium bicarbonate, which does not remove the salol. • 

In order to estimate salol in a mixture of copaiba and other oils, the 
sample is dissolved in ether, and extracted three times with 2J per cent 
sodium hydroxide. The alkaline solution is brought to the temperature 
of the steam-bath and held for five to ten minutes, and the balance of the 
determination conducted according to the following process: 

C. C. LeFebvre x has applied the bromin method to the determination 
of salol in tablets and powders: 

First extract the salol from a weighed portion of the powdered sample 
by means of 50 mils ether. In order to prevent moisture from collecting 
on the paper, use a short extraction thimble in an ordinary extraction 
tube, the ether being introduced by means of a separatory funnel, the stem 
of which passes through a stopper in the end of the tube. Run the sol- 
vent into a flask and remove the solvent by air blast. Then add 10 mils 
2| per cent sodium hydroxide and heat for five minutes at the temperature 
of the steam-bath. After this is complete dilute the alkaline liquid to 
about 200 mils, add an excess of potassium-bromide bromate solution, 
followed by 10 mils of concentrated hydrochloric acid. Shake the mix- 
ture for a minute, and then frequently during a half hour. At the end 
1 U. S. Dept. Agri. Bu. Chem. Bull. 162, p. 203. 



ORGANIC ACIDS— AROMATIC SERIES 685 

of this time add 10 mils of a 15 per cent potassium-iodide solution, and 
frequently agitate the mixture while it reacts for fifteen minutes. Titrate 
the free iodin with the thiosulphate solution which has been standardized 
against the bromin solution. From the number of cubic centimeters of 
the bromin solution expended, calculate the salol on the basis of 12 atoms 
of bromin to 1 molecule of salol. 

A few determinations made, where various excipients were added to 
the salol before saponification and allowed to remain throughout the 
titration, indicate that none of them except lactose interferes to any 
considerable degree. Even in this case, the quantity usually present 
would not throw the result off more than a few per cent. Tragacanth, 
Indian gum, acacia, lactose, starch, and dextrin were tried. This would 
seem to show that the method may be carried out directly on salol in the 
tablet, without previous extraction with ether. 

The reactions involved are the following: 

First, the salol is saponified to sodium or potassium salicylate and 
phenolate : 

HOCeHiCO • OC 6 H 5 +3KOH = KOCerLtCO • OK+C 6 H 5 OK+2H 2 

Phenol is attacked by bromin in excess to form symmetrical tribromo- 
phenolbromid : 

C 6 H 5 OH+4Br 2 = C 6 H 2 Br 3 OBr+4HBr 

Salicylic a.cid also forms the same product, inasmuch as the tribromo- 
salicyiic acid first formed is very unstable and loses its carboxyl : 

C 6 H 2 Br 3 OBr+2HI = C 6 H 2 Br 3 OH+HBr+I 2 

As a result, 12 atoms of bromide have been used up by 1 molecule 
of salol. 

The procedure for assaying mixtures of acetphenetidin and salol is 
described on page 859. 

Acetyl paramino phenylsalicylate 
CelLtOH • COOC6H4NHC.OCH3 

Salophen 

It forms small, white, crystalline leaflets or powder, odorless and taste- 
less, melting at 187 to 188° C, and containing 51 per cent of salicylic 
acid. It is almost insoluble in cold water, more soluble in warm water, 
but freely soluble in watery solutions of the alkalies and in alcohol, ether, 
and benzene, but not in petroleum benzine. 

If its alkaline solution be boiled it gradually becomes blue; on con- 
tinuing the boiling the color is discharged, but is again produced on cooling 



686 ORGANIC SUBSTANCES 

and exposure to air. On addition of ferric chloride to the alkaline solu- 
tion the violet color characteristic of salicylic acid is produced, but a 
simple aqueous solution of salophen does not react with ferric chloride 
and should not be changed by silver nitrate. 

Acetyl salicylic acid 
.OCOCHs 



CeH4< 

COOH 

Aspirin 

Aspirin forms small, colorless, crystalline needles, melting at 129-130°, 
odorless, and having an acidulous taste. It is soluble in 100 parts of water 
and freely soluble in alcohol, ether, chloroform, and glacial acetic acid. 
It is readily split up on boiling with water or with alkalies with the pro- 
duction of acetic acid and salicylic acid or a salicylate. 

It forms clear, colorless solutions with water, which do not develop a 
violet color on the addition of ferric chloride unless previously boiled or 
hydrolyzed by boiling with sodium hydroxide, or unless it stands for some 
time in the presence of cold water. It gives no reaction with silver nitrate, 
and should leave no residue when heated on platinum foil. 

When added to boiling water the odor of acetic acid is easily dis- 
tinguished. 

Acetyl salicylic acid may be removed from chloroform with alkalies 
and by sodium bicarbonate. If the former is used there may be a certain 
amount of hydrolysis and free salicylic acid results, but with bicarbonate 
in ice-cold solution the hydrolysis can be kept down to a minimum. 

Acetyl salicylic acid does not give a precipitate with bromin water, 
hence it is easy to detect the presence of free salicylic acid. Dissolve in 
alcohol, add a few drops hydrochloric acid, then bromin water until a 
permanent yellow color is obtained. If salicylic is present, the color of 
bromin will disappear at first, but no color will appear until dilution has 
reached a certain degree and finally the color of bromin persists and a 
precipitate agglomerates and settles. If acetyl salicylic is alone present, 
the color due to bromin does not disappear and no precipitate appears 
on dilution. 

Astruc finds that acetyl salicylic acid can be titrated accurately in 
dilute alcoholic solutions with potassium hydroxide and phenolphthalein 
without splitting off any of the acetyl group. From the acid number and 
saponification number the quality of commercial samples can be deter- 
mined. 

Dr. Emery found that aspirin of 100 per cent purity softened at 129.5° 
C. and melted from that temperature up to 130°. Mixtures of the pure 
substance with salicylic acid showed a tendency to soften several degrees 



ORGANIC ACIDS— AROMATIC SERIES 687 

below the melting-point, in some cases 10-20°, the material then remain- 
ing in a more or less pasty condition until the point of complete fusion is 
reached, which in the case of mixtures containing 60-85 per cent of salicylic 
acid extends over about 10°, the acid not dissolving readily in the melt, 
but remaining in solid form at the bottom and sides of the capillary. A 
mixture containing 58 per cent of aspirin melts sharply 115-116°, indicat- 
ing an eutectic mixture of about that composition. 

The estimation of free salicylic acid in acetyl salicylic acid may be 
accomplished by dissolving .1 gram of the sample in 1 mil of alcohol, 
followed by 48 mils of water and 1 mil of ferric chloride solution (1 volume 
of test solution U. S. P. to 100 volumes of water). The color is then 
matched against that produced by known amounts of a standard solution 
of sodium salicylate (.116 gram to 1 liter) made up to the same volume, 
and using the same quantity of reagent, 

Methyl Salicylate, C 6 H 4 OHCOOCH3 

Methyl salicylate is an exceptionally interesting substance, both on 
account of its varied uses, and the anomalous commerical conditions 
relating to it. It is used to a large extent as a flavoring agent, as an anti- 
septic and as an antirheumatic. In the trade it is sold under three names 
with widely divergent prices, depending on the designation. 

Methyl salicylate is widely distributed in nature, but is especially 
prominent in the leaves and the fruit of the wintergreen (Gaultheria 
procumbens) and in the stems and bark of the sweet birch (Betula lenta). 

also occurs in senega root (Polygala senega), Gaultheria punctata, 
and G. leucoceupa, and in small quantities in other plants. It probably 
is combined with other substances in the plant, but in a state where it is 
readily set free by the action of ferments, heat or water. 

The pleasant taste of the wintergreen plant probably first suggested 
its use in the form of an extract or essence for flavoring purposes, and, 
as the commerce grew and with it a demand for a purer product, the highly 
rectified oil containing the essential flavoring agent was gradually evolved. 
Owing to the increasing demand for the oil, and the comparatively limited 
amount of the plant, the hunt for other sources of crude material was 
started, and the oil distilled from sweet birch came into the trade. Finally 
the chemical composition of the oil was established as methyl salicylate, 
and after synthetic salicylic acid came to be a commercial possibility, it 
was but another step to prepare the methyl ester, and the latter is now 
made in a large way. 

After salicylic acid was found to have a physiological and therapeutic 
importance, the medical profession seemed to prefer the natural product 
to the synthetic, but later, when processes of manufacture became more 



688 ORGANIC SUBSTANCES 

refined and no chemical difference existed between the two, this prejudice 
began to wane. 

The oil prepared from wintergreen and rectified contains a small 
quantity of a mixture of substances which appear to give it a shade of 
flavor differing slightly from the ester made directly from salicylic acid, 
and the same possibly applies to the oil from birch, though to a much 
less extent. The condition as regards the flavor is probably analogous 
to that existing between what is known as straight and rectified whisky. 
Chemically, these three products are practically the same, the wintergreen 
oil being the less pure. The anomalous condition is manifested forcibly 
in the price, for wintergreen sells for $6 to $7 per pound, birch for $5.50 
to $6, and the synthetic for about $0.65 to $0.70. 

In the trade the following classifications are in vogue: oil of winter- 
green leaf, oil gaultheria prepared from Gaultheria procumbens and now 
practically off the market: oil betula, oil of wintergreen from Betula 
lent a: methyl salicylate, synthetic or artificial oil of wintergreen. 

In a chemical sense, all of these terms are practically synonymous, 
and in the last edition of the Pharmacopoeia they are all grouped together 
under the one heading Methyl Salicylate. 

Some oils will be encountered having a red color, which has been 
attributed to iron, but it is doubtful if that metal is responsible for the 
coloration. If a red oil is dissolved in ether and shaken with dilute potas- 
sium hydroxide and the resultant alkaline solution neutralized, a colorless 
oil will be obtained. It is probable that the color is due to the same cause 
which produces a pink tint in phenol when it has stood for some time and 
which has been conclusively proven to be due to other causes than iron. 

Power and Kleber investigated the oils of gaultheria and betula, with 
special reference to the products other than methyl salicylate. They 
found that Gaultheria contained 99 per cent of the ester, and Betula 99.8 
per cent. In order to obtain the impurities, the oil was dissolved in ether 
and shaken with 7.5 per cent aqueous solution of potassium hydroxide 
to remove the methyl salicylate, leaving the other constituents in the ether. 
From gaultheria, these constituents were obtained as a semi-solid mass 
consisting of a paraffin melting 65.5°; an aldehyde or ketone with an odor 
like oenanthic aldehyde; a secondary alcohol (CgHieO) boiling 160-165°; 
and an ester which on saponification yielded the above alcohol, and an 
acid, C6H10O2. The alcohol and ester possessed the penetrating character- 
istic odor which gives the peculiar shade of aroma to Gaultheria oil. 

From Betula the same constituents minus the secondary alcohol were 
isolated. 

The author had occasion at one time to study the problem of differenti- 
ating between the three products, and he came to the conclusion that 
there was practically no chemical method which would enable the analyst 



ORGANIC ACIDS— AROMATIC SERIES 689 

to assert beyond question that there was any difference. An empirical 
procedure was used as a makeshift, on account of the practical problem 
which developed from the use of the oils in which the sample was treated 
with an excess of sodium hydroxide and left overnight in a stoppered flask. 
If the odor noticeable was then of a peculiar musty character, the product 
was deemed to be natural oil, or at least to contain some of the natural 
product. 

At one time there was communicated to me by the Bureau of Chemistry 
a method of differentiation based on the color given by mixing oil with 
vanillin and sulphuric acid. It is directed to dissolve 7 drops of the oil 
in 10 mils of a 5 per cent alcoholic solution of vanillin, and on the addi- 
tion of 1 mil concentrated sulphuric acid, a dark red color appears in the 
case of oil of Gaultheria, changing to blue on the addition of 2 volumes 
of alcohol. Methyl salicylate gives a yellow color. 

I have tried this method with commercial oils and artificial methyl 
salicylate, and have found that they all react in the same way, all giving 
the final blue color, changing to a purplish brown after twenty-four hours. 
Later I experimented with samples of Betula oil according to the procedure 
of Power and Kleber, and, after recovering that portion of the oil which 
was not removed by alkali from ether, I tested it according to the vanillin 
reaction and obtained the same blue color, which in this case was very 
deep and did not change to purplish brown for several days. It is evident 
that the color-producing material exists in the impurities, and, from further 
work done, that it is an unsaponifiable constituent. 

For assaying methyl salicylate, the following methods are recommended 
as giving reliable results. 

U. S. P. Assay Method. — Introduce about 2 mils methyl salicylate 
into a tared flask. Note the exact weight, add 50 mils of half-normal 
alcoholic potash, connect the flask with a reflux condenser, and heat the 
mixture on the water-bath during two hours. Then add a few drops of 
phenolphthalein and titrate the excess of alkali with half-normal hydro- 
chloric acid. 

Each mil of N/2 alcoholic potash consumed corresponds to .07603 
gram methyl salicylate. 

Assay of Methyl Salicylate. — Weigh 1 gram in a closed weighing-tube, 
and transfer to a 100-mil graduated flask, washing out the weighing tube 
with alcohol, add 20 mils sodium hydroxide 10 per cent and heat to boiling 
for two hours. Cool and make up to 100 mils. Remove an aliquot of 
10 mils, evaporate any alcohol, transfer to 200-mil Erlenmeyer, add a 
slight excess of hydrochloric acid, then 1 gram anhydrous sodium car- 
bonate, 100 mils water, and heat nearly to boiling. Add 35 to 50 mils 
N/5 iodin (approx. standard), digest on steam-bath for one hour, adding 
iodin from time to time, if necessary Then add a few drops sodium 



690 ORGANIC SUBSTANCES 

thiosulphate to destroy the excess of iodin, decant liquid on a tared Gooch, 
digest precipitate in flask with 5 mils hot water for ten minutes, filter, 
and wash with hot water, using about 150 mils. Dry and weigh. 

Weight X .4658 X .95 X 10 = weight of methyl salicylate. 

When methyl salicylate occurs in admixtures with other substance of 
a volatile nature, its determination will depend largely on the nature of 
the combination. If the other substances are saponifiable to acids capable 
of ready separation from salicylic acid, the problem is not difficult. 

If the sample under examination is a liquid, a measured quantity is 
transferred to a separator, diluted with water, sodium chloride added, 
and the soluble oils shaken out with petroleum ether. The solvent, after 
washing with saturated salt solution is poured into a mixture of alcoholic 
potash or soda and heated under a reflux for one hour. The alcohol 
is then removed by evaporation, and the salicylic acid recovered from 
the alkaline liquid and either weighed or titrated. The methyl salicylate 
can then be calculated. If other acids are present at this stage, they can 
be separated by the procedures given under the discussion of salicylic 
acid. 

If the methyl salicylate and salicylic acid occur together in the same 
mixture, a chloroformic or ethereal solution of the two should be shaken 
with dilute sodium bicarbonate to remove the acid before attempting to 
determine the ester. 

For the determination of methyl salicylate in flavoring extracts or in 
spirit of gaultheria, the method of Hortvet and West 1 will be found to 
give good results. 

Measure 10 mils of the extract into a 100-mil beaker, add 10 mils of 
10 per cent potassium hydroxide solution, and heat the mixture over a 
boiling water-bath until the odor of oil of wintergreen has disappeared 
and the liquid is reduced to about one-half its original volume. By this 
treatment the methyl salicylate is converted into the potassium salt. 
Liberate the salicylic acid by the addition of an excess of 10 per cent 
hydrochloric acid, cool, and extract in a separatory funnel with three por- 
tions of 40, 30, and 20 mils of ether respectively. Pour the combined 
ether extracts through a dry filter into a weighed dish, wash the filter 
with 10 mils of ether, evaporate filtrate and washings slowly at 50° C, 
dry one hour in a desiccator, and weigh. The per cent of wintergreen 
oil by volume (M) is obtainable from the weight of salicylic acid (S) by 
the following formula; 

1.101X10XS 
1.18 

1 J. Ind. Eng. Chem., 1, 1909, 90. 



ORGANIC ACIDS— AROMATIC SERIES 
DERIVATIONS OF HYDROXY BENZOIC ACIDS 


691 


Methyl p-amido m- 
hydroxy benzpate . . . 


/OH 3 
CgH/-NH 2 4 

\COOCH 3 1 


Orthoform 


120° 


Spar. sol. 


Antiseptic, 
local anes- 
thetic 


Sodium Salt of Methyl 
p-amido m-hydroxy- 
benzo-sulphonate. . . 


C7H30 3 (S0 5 Na)(NH2) 
(CH 3 )+H20 


Sulphonated 
Orthoform 


269° 


Readily sol. 




Methyl m-amido-p- 
hydroxy benzoate . . . 


/COOCH3 1 
C 6 H 3 (-OH 4 
\NH 2 3 


New Orthoform 


142° 


Somewhat 
sol. 


Antiseptic, 
local anes- 
thetic 



These substances are derivatives of the acids isomeric with salicylic 
acid. Their properties have been fully described in the chapter on Anes- 
thetics. 

COUMARIC ACIDS, C 6 H 4 (OH)CH = CHCOOH 

Three forms, known as 1-2,1-3, 1^. 

The 1-2 form occurs in the leaves of species of Melilotus, sweet clover, 
and in Angraecum fragrans. It forms colorless crystals, melting 208°, 
with decomposition. It is freely soluble in water and alcohol, and gives 
a flourescent solution with alkalies. This acid is converted to salicylic 
and acetic acids on fusion with potassium hydroxide, but on boiling in 
alkaline solution it is converted to coumarin. Nascent hydrogen converts 
it to melilotic acid. 

The 1-A acid occurs as an ester in Cape aloes, in the resin of Picea 
vulgaris, and is one of the products of hydrolysis of naringin, 

Coumarin, C 6 H 4 OCOCH = CH 

Coumarin or " Tonka-bean camphor " occurs in Tonka, the seed of 
several species of Dipteryx, also in the leaves of Liatris odoratissium and 
those of several other plants. 

It forms colorless crystals, melting 67°, with an odor suggestive of 
vanillin, but nevertheless highly distinctive, recalling freshly mown sweet 
grass. It is sparingly soluble in cold water, somewhat in cold alcohol, 
not readily in hot alcohol and in ether. 

It is readily distinguished from vanillin as it is not removed from an 
ethereal solution by caustic alkali. 



Melilotic Acid, C 6 H 4 (OH)CH 2 COOH 

Melilotic acid is 1-2 hydrocoumaric acid, and its close relationship is 
readily noted by a glance at the formula. It is present with coumarin 



692 ORGANIC SUBSTANCES 

in Melilotus officinalis — sweet clover. It melts 82 to 83°, gives a bluish 
color with ferric chloride, yields acetic and salicylic acids on fusion with 

yCH2 — CH2 

potash, and hydrocoumarin CqH4\ on distillation. 

X)CO 



FERULIC ACID, C 6 H 3 (OH)(OCH 3 )CH = CHCOOH 

Ferulic or m-methoxy-p-hydroxycinnamic acid occurs in several resins 
including opoponax and asafetida. It may be obtained from the latter 
by treating the alcoholic solution with alcoholic lead acetate which pre- 
cipitates the lead ferulate. The lead salt may then be decomposed with 
dilute sulphuric acid, and the regenerated acid crystallized out of hot 
alcohol. 

It reduces Fehling's solution and gives a brownish precipitate with 
ferric chloride, which must not be confused with the buff-colored pre- 
cipitate obtained with benzoate. 



TOLUIC ACID DERIVATIVES 

Betanaphthol-Hydroxytoluic Acid 

C 6 H3(OH)(COOH)(CH 2 C 10 H 6 OH) 2:3:1 

Epicarin 

It forms colorless or yellowish needles, melting at 190 to 195° C, 
difficultly soluble in water, but easily soluble in alcohol, ether, acetone, 
and in soaps. It dissolves in oils on the addition of a little ether. It 
has the character of a strong acid, forming well-crystallized salts, which, 
however, are sparingly soluble in water, particularly the sodium salt. On 
exposure to air it acquires a reddish color due to oxidation; if it is then 
recrystalhzed from glacial acetic acid, colorless crystals are again obtained 
which melt at 166° C. These, however, retain a little acetic acid, but 
lose this by heating at 120° C. 

The alcoholic solution of epicarin develops an intense blue color with 
ferric chloride. When heated with concentrated sulphuric acid, a red- 
brown solution, having a vivid green flourescence, is produced. If shaken 
with chloroform and solution of potassium hydroxide, a yellowish color, 
changing later to yellowish green is developed, thus distinguishing epicarin 
from beta-naphthol, which produces a deep blue color under the same 
conditions. 

Epicarin is an antiseptic and parasiticide, and is used in the treatment 
of skin diseases, particularly scabies, and eczema. 



ORGANIC ACIDS— AROMATIC SERIES 693 

Protocatechuic Acid 

This acid occurs to some extent naturally both in the free state and 
in combination. It is obtained on fusing or saponifying some of the resins 
such as catechu, gum benzoin, gum kino, etc. It forms needle-like crys- 
tals melting 195-199°, readily soluble in water, alcohol, ether, and petro- 
leum ether. Its aqueous solution gives a green color with ferric chloride 
changing to blue and dark red on adding veiy dilute sodium carbonate. 
A neutral solution of a protocatechuate gives a violet color with ferric 
chloride which might be mistaken for the salicylate reactions. Proto- 
catechuic acid gives a precipitate with lead acetate and reduces silver- 
nitrate on warming. 

GALLIC ACID 

Gallic or pyrogallol carboxylic acid, C 6 H 2 fOH)3COOH 1.2.3.5, is a 
trihydroxybenzoic acid. It occurs in gall nuts and various vegetable 
products and is prepared by boiling tannic acid with a dilute acid. It 
crystallizes in needles with 1 mol. water which melt with decomposition at 
220°, pyrogallic acid and carbon dioxide being obtained. It dissolves in 
water, alcohol, ether, chloroform, and etlryl acetate and its aqueous solu- 
tion gives a bluish-black color or precipitate, with ferric chloride soluble 
in excess of the reagent to a green color. The exact color is affected by 
the concentration of the solution and often the green tint will be the only 
one obtained due to the small quantity of the sample. It is a strong 
reducing agent and precipitates gold, silver, and platinum from solutions 
of their salts. 

Gallic acid can be removed from its aqueous acid solution by ether, 
thus differing sharply from tannic acid. 

Gallic acid is used in medicine as an antiseptic and hemostatic. It 
will be found in foot powders and tablets, in pile remedies, in certain 
gonorrhea mixtures, and in internal remedies for intestinal hemorrhage, 
night sweats, hematuria, pyrosis, etc. It is combined with opium and 
Hydrastis in menorrhagic tablets. 

On adding calcium hydroxide solution to a cold concentrated solution 
of gallic acid, a bluish-white precipitate will form where the test solution 
is temporarily in excess and will disappear on shaking. When the reagent 
has been added in excess the precipitate no longer dissolves, and the liquid 
acquires a tint which is blue by reflected and green by transmitted light, 
and becomes pink on the addition of a large excess. 

With tannic acid the precipitate first formed is pale bluish white and 
does not dissolve on shaking. It deepens in color when an excess has been 
added and the solution becomes pinkish with a large excess. 



694 ORGANIC SUBSTANCES 

Gallic acid gives no precipitate with gelatin, alb" min or the common 
alkaloids, differing in all these particulars from tannic acid. 

Gallic acid is not precipitated from solution by bromin water nor by 
bromide-bromate reagent. With dilute hydrochloric acid and formal- 
dehyde no precipitate appears at first, but on standing it comes down. 
Tannic acid reacts in the same way. Gallic acid gives a light-yellow 
precipitate with lead acetate. 

Neither acid can be titrated with alkali. 

Though it gives no precipitate with bromin, there is some reaction in 
solution for on subsequently recovering the acid product with ether, it 
no longer gives the characteristic color with ferric chloride. 



GALLOGEN 
C 6 H(OH) 2 

CO O 



C 6 (OH) 2 -COOH 

Ellagic Acid 

is anhydrous ellagic acid prepared from Divi-divi, the pods of Caesalpina 
coriaria. 

It is a yellowish, odorless, tasteless powder, insoluble in all acid and 
neutral liquids, but soluble in alkaline liquids to the amount of 2 per cent, 
such solutions being, however, very readily oxidized. 

Its solutions in alkaline media give all the reactions of tannic acid 
with iron salts, gelatin solution, etc. With fmning nitric acid it gives a* 
characteristic dark red color. 

Gallogen is an astringent and antidiarrhetic and is used in dysentery, 
cholera infantum, and diarrhea. 

Bismuth subgallate, sometimes called " Dermatol," is a yellowish 
powder of somewhat variable composition and may yield from 52 to 57 
per cent Bi2C>3 on ignition. It is insoluble in water, alcohol, and ether, 
but is readily soluble in hot mineral acids and alkali hydroxides, forming 
with the latter a clear yellow solution rapidly turning red. 

If the salt is agitated with hydrogen sulphide water, a black precipi- 
tate of bismuth sulphide is obtained, and on filtering and boiling off the 
excess of hydrogen sulphide from the filtrate, the cooled liquid will give 
a blue-black color with ferric chloride. 

Aluminum gallate, known as Gallal, is soluble in ammonia. 

Bismuth oxyiodomethyl gallate or iodogallicin is a dark-gray powder 
used as a substitute for iodoform. 



ORGANIC ACIDS— AROMATIC SERIES 695 



Galloformin 

This substance is a reaction product of gallic acid and hexamethylene 
tetramine. It is slightly soluble in water, alcohol, ether, and glycerin, 
and is decomposed by heat. It is used as an antiseptic. 

Gallanilide or Gallanol, C 6 H 5 NHCOC 6 H 2 (OH) 3 +2H20 

Gallanol is a brownish crystalline powder, melting 205° C, soluble in 
alcohol, ether, and boiling water, insoluble in chloroform and benzol. It 
is employed externally as an antiseptic and astringent. 

Gallicin, or Methyl Gallate 

This substance is a grayish- white crystalline powder, melting 202°, 
soluble in alcohol, ether, and hot water. It is used in eye and throat 
troubles to relieve inflammation and congestion. 

Gallobromol, C 6 Bi 2 (OH) 3 COOH 

Dibromogallic acid is a light-brown powder, melting 140-150° C, sol- 
uble in alcohol, ether, and water. It is used internally as a substitute 
for potassium bromide and externally as an astringent and antiseptic. 

Gallotannic Acid 

This acid is probably the anhydride of gallic acid, as it is resolved into 
the latter by boiling with dilute sulphuric acid. 

Ci 4 Hio09+H20 = 2C 7 H 6 05 

The pure acid is an almost colorless amorphous substance which dis- 
solves readily in water, alcohol, and glycerin, somewhat soluble in ethyl 
acetate, and almost insoluble in ether and chloroform. It is removed 
from its acid aqueous solution to a very slight extent by ether, but is 
taken up gradually by ethyl acetate, especially if the solution is saturated 
with salt. Its aqueous solution gives a blue-black precipitate with ferric 
chloride, with most alkaloids including cinchonin, and with gelatin. It 
is completely precipitated by lead acetate, and this property furnishes a 
means for its quantitative estimation. It is also removed from its aqueous 
solution by hide powder and by this means can be separated from citric 
or tartaric acids. 

Tannic acid is used for the same purposes as gallic acid and is valuable 
in chronic diarrhea and as an antidote in alkaloidal poisoning. It is used 



696 ORGANIC SUBSTANCES 






to a considerable extent in pile remedies, where it is combined with opium, 
camphor, menthol, boric acid, etc. Combined with glycerin it forms an 
efficient gargle for sore throat. Iodotannic acid used in gonorrheal injec- 
tions consists of an alcoholic solution of tannic acid and iodin. 

The commercial acid is often impure, containing varying amounts 
of foreign or transformation products insoluble in water. 

In order to determine tannic or gallic acids a procedure based on that 
recommended by the writer for tea may be advantageously employed. 
Lead tannates contain definite quantities of lead, and if a solution contain- 
ing the acid is precipitated by a known quantity of lead acetate in excess, 
and the lead remaining in solution determined, it is a simple matter to 
arrive at the amount of tannic acid. To carry out this procedure properly 
one must know the lead content of the tannate yielded by the drug in 
question, and this will naturally require a certain amount of research, for 
it will first be necessary to prepare the tannin in the pure condition. In 
the case of tea tannin the lead content is 48.3 per cent. 

The following method will enable one to obtain a very accurate esti- 
mation of the quantity of tannic acid in tea: 

Ten grams of powdered tea are transferred to an Erlenmeyer of 100- 
mils capacity, 50 mils petroleum ether added, stoppered, and shaken 
occasionally and allowed to stand overnight. It is then filtered through 
a dry filter and the flask and filter washed with petroleum ether until the 
filtrate comes through colorless. The powder is dried, returned to the 
flask, treated with 50 mils of 50 per cent alcohol, shaken from time to time, 
and allowed to stand overnight. It is filtered into a 500-mil graduated 
flask and filter washed with three portions of hot 50 per cent alcohol. 
After cooling, an excess of 10 per cent lead acetate solution is added 
(usually 50 mils will be sufficient), the mixture well shaken, made up to 
mark with -50 per cent alcohol and thoroughly mixed. As soon as the 
precipitate has settled, leaving a clear supernatant liquid, 10-mil portions 
are pipetted, concentrated over the steam-bath to drive off the alcohol, 
treated with 1 to 2 mils of dilute sodium hydroxide, washed into a small 
beaker, and submitted to the action of hydrogen sulphide. As soon as 
the precipitation is complete, the lead sulphide is filtered into a tared 
Gooch, washed with water, and dried in vacuo over sulphuric acid. 

At the same time, a blank is run, using the same quantity of lead 
acetate made up to 500 mils, the difference in the lead sulphide figures, 
of course, being a measure of the lead taken up by the tannin. In this 
compound the lead amounts to 48.3 per cent, and it is thus a simple matter 
to figure the percentage of tannin. 

Tannic acids are widely distributed in the plant world, and reactions 
for them will be obtained in most mixtures containing vegetable constit- 
uents. The study of the different tannins occurring in the medicinal 



ORGANIC ACIDS— AROMATIC SERIES 697 

plants has hardly commenced. Their presence in mixtures is best detected 
in the aqueous alkaline solution after the shaking-out process. The liquid 
should be evaporated until the ammonia is driven off, lead acetate added 
in excess, the precipitate filtered, washed, and decomposed in the presence 
of alcohol to which a trace of ammonia has been added. On filtering 
and evaporating the alcohol the tannate will be left as an ammonium 
salt, and will give the characteristic tannic acid reactions. 

Tannalbin 

Tannate of albumin is a compound of tannic acid and albumin. 

It is a fight-brown, odorless, and tasteless powder, containing about 
50 per cent of tannic acid. It is practically insoluble in water or alcohol 
but slowly soluble in alkaline fluids, which split it up into its constituents. 

It is employed as an astringent in diarrhea. 

Tannigen 

Diacetyl-tannin is tannyl acetate, (CHsCO^CmHsOo, the acetic acid 
ester of tannin. 

It is a light-gray, almost odorless and tasteless powder, which undergoes 
no change when heated alone, even to 180° C, but softens when heated 
in water at 50° C. It is practically insoluble in cold water, scarcely solu- 
ble in hot water, but soluble in alcohol, and also in solutions of borax, 
sodium phosphate, sodium carbonate, lime, etc., being precipitated from 
these solutions b} r acids. It is rapidly saponified by boiling sodium or 
potassium hydroxide solutions, or gradually in the cold, into acetic and 
gallic acids, while ammonia produces acetic and tannic acids. 

Its aqueous solutions produce with ferric salts a green color, instead 
of the blue- violet color characteristic of tannic acid. A slightly alkaline 
solution in sodium phospate exhibits all the characteristics of an astringent 
and precipitates albumin, but these properties are destroyed by borax 
or more alkali. 

Protan — Tannin Nucleo-Proteid 

Protan is said to be a chemical combination of casein with tannic acid 
containing about 50 per cent tannic acid. 

When shaken with water and filtered, a colorless solution should be 
obtained, which should give not more than a faint trace of color with 
ferric chloride solution, showing absence of more than traces of free (uncom- 
bined) tannic acids. 

The resistance of Protan to the action of the gastric juice may be 
shown by mixing 2 grams (dried at 100° C.) with 40 mils ,2 per cent hydro- 



698 ORGANIC SUBSTANCES 

chloric acid containing ten times the theoretical amount of 1 : 3000 pepsin 
necessary to digest the proteid present, warming to 40° C. for six hours, 
filtering off the residue, drying and weighing; 60 to 70 per cent of the 
amount taken may thus be recovered. 

The tannin may best be determined by difference, the casein being 
determined by decomposing it by the Gunning method and estimating 
the nitrogen. 

It is employed as an intestinal astringent in all forms of diarrhea. 

Tannismuth 

Bitannate of bismuth is the bismuth salt of tannic acid in which 
approximately one atom of bismuth is combined with two molecules of 
tannic acid having approximately the formula, Bi(OH)(Ci4H 9 09)2, and 
containing between 17 and 21 per cent bismuth. 

It is a light yellow powder with slightly astringent taste, insoluble 
in water, soluble in cold caustic alkalies, and in diluted hydrochloric acid. 

Tannismuth is used in chronic intestinal catarrh. 

Tannoform 

Tanninformaldehyde or methylenditannin, CH^CuHgOg^, is a con- 
densation product of formaldehyde with gallotannic acid. 

It forms a voluminous, reddish powder, odorless and tasteless. It 
is insoluble in water, but soluble in alkaline liquids and in alcohol. 
One one-hundredth gram of tannoform dissolved in 2 mils concentrated 
sulphuric acid forms a brown solution which on warming becomes green 
and later changes to blue. The green or blue solution, on addition of 
alcohol, assumes a brilliant blue color, which gradually changes to wine 
color, while on addition of dilute sodium hydroxide the color is pale green. 

Tannopin 

Hexamethylene-Tetramine-Tannin, or Tannon, (CuHgOg^CE^eN^ 
is a condensation product of tannin with hexamethylenamine. 

It is a fine, fawn-colored, odorless and tasteless, non-hygroscopic 
powder, containing 87 per cent of tannin and 13 per cent of hexamethyl- 
enamine. It is insoluble in water, weak acids, alcohol, chloroform, or 
ether, but slowly soluble in dilute alkalies. On heating dry tannopin, 
it swells and gives off the odor of formaldehyde. The odor of formal- 
dehyde is also developed on heating tannopin with dilute sulphuric or 
hydrochloric acid, while on boiling with sodium hydroxide solution it 
splits off ammonia. The clear aqueous filtrate from tannopin does not 
give a reaction with ferric chloride. 

It is used in intestinal catarrh. 



ORGANIC ACIDS— AROMATIC SERIES 699 



Tanosal 

Tanosal, creosal, or creosote tannate, is obtained when birchwood 
creosote and tannic acid are heated with phosphorus oxy chloride. It is 
a dark-brown powder with a creosote odor, soluble in water, alcohol, and 
glycerin, but insoluble in ether, and used as an astringent and antiseptic. 

Bismuth oxyiodotannate or ibit is a product of uncertain composition, 
used as a substitute for iodoform. 

Pankreon is obtained by the action of tannin on pancreatic substances. 
It is soluble in alkaline li quids but not in water or acids, and is used in 
some forms of intestinal dyspepsia, gastritis, and carcinoma. 

Gorter found that the tannic acids ascribed to many plants are in 
reality chlorogenic acid, C32H 38 0ig. This body is a dibasic acid, crystal- 
lizing in white anhydrous needles, melting 206-207°, having an astringent 
and slightly acid taste. It is soluble in water, ethyl and isobutyl alcohol, 
and acetone, slightly soluble in ether and acetic ether, insoluble in chloro- 
form and carbon tetrachloride. Laevograte (a) D = -33°1. 

Alkalies in excess color it yellow. It can be determined by titration 
with alkali, the end-point being marked by a yellow color. With ferric 
chloride it gives a green color changing to blue and to violet, red on addition 
of sodium hydroxide. Warmed with sulphuric acid and manganese 
dioxide the odor of quinone is given off. It reduces silver nitrate on warm- 
ing, but Fehling's solution only slightly. Exposed to the fumes of ammonia 
in the air its solutions are first yellow gradually become green. 

In alcoholic solution it is precipitated yellow by alcoholic potash and 
by lead acetate. It gives well-defined crystalline salts with calcium, mag- 
nesium, zinc, lead, benzidine, and strychnin. 

It exists in coffee as the double salt of caffein and potassium, colorless, 
crystalline prisms, becoming yellow at 150° and charring without melting 
at 225°. The caffein is not removed by chloroform in the dry state, but 
when water is present it is separated. 

On boiling with potash it is hydrolyzed to caffeic and quinic acids, 

C32H38O19H2O = 2C9H8O4+2C7H12O6. 

On acetylization a crystalline body is formed having 5 acetyl groups: 
Ci6Hi 8 09(C9H 3 0)5. The group CieNisOg is called by Gorter hemichloro- 
genic acid, and is considered as proceeding from the decomposition of 
chlorogenic acid with the loss of one molecule of water. 






C32H38O19 = H20-r2Ci6Hi809. 



In its turn hemichlorogenic acid is decomposed by alkalies or acids into 
one molecule of quinic and one molecule of caffeic acids. 



700 ORGANIC SUBSTANCES 

Chlorogenic acid would then be formed from two molecules of quinic 
and two of caffeic acids without the least trace of carbohydrate. 
Caffeic acid is 3-4 dioxycinnamic acid 

OH x 

>C 6 H3-CH = CHCOOH 
OBK 

It melts at 194-195°, gives a yellow color with ferric chloride, becoming 
reddish violet on adding sodium hydroxide. It is colored yellow by 
ammonia, reduces silver nitrate and gives a yellow precipitate with lead 
acetate. 

Quinic acid is tetraoxyhexahydrobenzoic acid. 

C 6 H 7 (OH) 4 COOH 

It melts at 161°, is lsevogyrate, soluble in water, and gives a white 
precipitate with neutral lead acetate but none with basic. 

Quinic acid has medicinal uses, being employed in uric acid diathesis 
in the form of salts, the most important being Uthium qumate or urosin, 
piperazin quinate or sidonal, hexamethylenetetramine quinate or chino- 
tropin, and urea quinate or urol. 

For the detection of the acid in plants, the following color reaction 
is used: 

Ten grams of leaves are boiled with 50 mils of dilute hydrochloric 
acid during one hour in a reflux apparatus. The filtrate from this is shaken 
with 15 mils of ether. The latter is washed with a dilute solution of sodium 
hydrogen carbonate and then twice with water, and to it is added a small 
quantity of a very dilute solution of ferric chloride, when, if chlorogenic 
acid is present in the leaves, a violet coloration is produced in the aqueous 
layer on shaking, while the ethereal layer develops a yellow tint. Out 
of 230 species of plants examined by Gorter in this way, 98 gave a positive 
result. The acid appears to occur in many plants of the orders Acanthacece 
Araliaceoe, Convolvulacece, Boraginacece, Gesneraceoe, and Composite. 

Gorter's experiments also proved that the acid of Nux Vomica, formerly 
known as igasuric acid, was identical with chlorogenic acid. 

VEGETABLE ACIDS USED MEDICINALLY 

There are a few other acids occurring in drugs which are extracted in 
a more or less pure state and used for their medicinal properties. They 
are more conveniently considered under the discussion of the individual 
drugs, but attention will be called to them at this point. 

Anacardic acid, from Anacardium occidentale (cashew nut), used as 
a vermifuge in the form of its ammonium salt. 



ORGANIC ACIDS— AROMATIC SERIES 701 

Embelic acid, from the fruit of Embelia ribes, soluble in alcohol, 
ether, and cholorofonn, and used as a tape-worm expellant. 

Filicic acid, from Malefern, used for the same purpose. 

Caincic acid, from the root of Chiococca anguifuga or C. racemosa 
(Cainca root), soluble in alcohol and ether, and used in dropsy as a diuretic 
cathartic. 

Quillaic acid, from the inner bark of Quillaja saponaria (soap bark), 
soluble in alcohol and water and used as an expectorant. 

ARABIC ACID, C 6 H 10 O 5 +H 2 O 

Arabic acid'br arabin occurs in gum acacia, and may be obtained by 
dissolving the gum in water, adding hydrochloric acid and precipitating 
with alcohol. Its aqueous solution is acid in reaction and on evaporation 
leaves a vitreous mass which loses water above 120°, yielding metarbin. 
The latter does not dissolve but swells in water. 

THE AROMATIC GUM-RESINS AND BALSAMS 

The chemistry of the aromatic gum-resins and balsams is intimately 
connected with the chemistry of benzoic and cinnamic acids. The drugs 
themselves are complex mixtures, and no definite standards have been 
ascribed to them, in fact with the possible exception of gum benzoin it 
is doubtful if many of the analytical figures obtained and reported were 
obtained with pure products, collected under personal observation, and 
any data quoted must be taken with reservation. 

The quantitative estimation of these drugs as a whole is really of 
little moment in comparison with the importance of estimating the amount 
of the potent ingredients in such products as Xux Vomica, aconite, etc. 
If a quantitative value is important, it may be confined to the determi- 
nation of the aromatic acids in the free and combined condition, and as a 
matter of fact this is about all that can be accomplished with the pure 
drugs themselves, except where they are grossly adulterated and an approx- 
imate determination of the adulterant is desired. 

The drug chemist often finds it necessary to pass upon the quality of 
a specimen of gum or resin, hence we will first discuss the properties and 
the composition of the individual drugs in the light of our present knowledge 
concerning them, and before proceeding with a detailed study of the com- 
position, the worker should familiarize himself with the names and signifi- 
cance of the esters of benzoic and cinnamic acids which will figure largely 
in any work he will take up. These include: 

Benzyl benzoate. 

Benzyl cinnamate. Cinnamein. 

Cinnamyl benzoate. 

Cinnamyl cinnamate. Styracin. 



702 ORGANIC SUBSTANCES 

The term " cinnamein " is applied not only to the ester benzyl cinna- 
mate, but to the mixtures of esters, alcohols and other substances existing 
in the balsams of Peru and Tolu which are not extracted from an ethereal 
solution by alkalies. This point must be borne in mind constantly by 
the analyst, because its application may become a matter of importance 
in legal work. 

Gum Benzoin 

Gum benzoin, according to the Pharmacopceia, comes from the 
Styrax benzoin (Styracese) and probably other species of Styrax, but the 
researches of Holmes and those of Rordoff indicate that Siam benzoin 
comes from S. tonkinense. The trees producing it grow in the East 
Indies and Southern Asia and as far as can be determined different 
commercial grades of gum, Penang, Sumatra and Siam all come from the 
same plant. 

Gum benzoin is the source of natural benzoic acid. Medicinally it is 
employed as a stimulant and expectorant in pectoral troubles and as a 
soothing lotion for wounds, fissures, bed sores, etc. 

Traumatic balsam, Turlington's balsam or Friar's balsam consists of 
an alcoholic solution of benzoin, storax, Peru and Tolu balsams, alces, 
myrrh, and angelica root, sometimes with licorice. Compound tincture 
of benzoin contains benzoin, aloes, storax, and Tolu. 

Mixtures similar in composition to Friar's balsam have been known at 
different times as Jesuit's drops, Wade's balsam, baume de commandeur, 
etc. These " baumes " will often be encountered by those who work 
with imported preparations. 

Benzoinated lard is prepared by incorporating fluid benzoin with pure 
lard or by digesting hot lard with powdered gum and then straining. 
This substance will often be found in salves and ointments mixed with 
various ingredients such as menthol, oil of mustard, Capsicum, etc. 

Sumatra Benzoin 

The drug occurs in irregular masses composed of yellowish or reddish- 
brown tears of Variable size, and a reddish-brown and translucent or 
grayish-brown and opaque matrix; it is brittle and the tears are milky 
white internally. The drug becomes soft on warming and benzoic acid 
is yielded on sublimation; the odor is agreeable and balsamic, resembling 
that of storax, and the taste is aromatic. The mass often contains con- 
siderable quantities of imbedded bark. 

Pelembang benzoin resembles the Sumatra, but is somewhat more 
transparent. 

Penang benzoin resembles the Sumatra in appearance, but resembles 
the Siam more in composition. 



ORGANIC ACIDS— AROMATIC SERIES 703 

Siam Benzoin 

This drug occurs in concavo-convex white tears, often imbedded in 
a rich amber-colored translucent resin, with more or less admixed bark. 
The finer varieties are composed almost entirely of these tears loosely 
agglutinated together. It has a vanilla-like odor and a bitter taste. 

Constituents of Sumatra Benzoin. — It is made up of about 75 per 
cent of a resinous substance, benzoresin, which consists of two esters, 
one an ester of cinnamic acid and resinotannol amounting to 90 per cent 
or more of the benzoresin, and the other an ester of cinnamic acid and 
benzoresinol. Benzoresin on saponification yields 30 per cent cinnamic 
acid, 65 per cent of resinotannol, and 5 per cent benzoresinol. 

Sumatra benzoin also contains traces of benzaldehyde and benzol, 
.1 to 1 per cent of vanillin, 1 per cent phenypropyl cinnamate, 2 to 3 per 
cent of styracin (cinnamyl cinnamate) and 14 to 17 per cent of insoluble 
matter, mostly woody tissue. 

Constituents of Siam Benzoin. — It is composed largely of a resinous 
substance, siabenzoresin, consisting of 90 per cent of an ester of benzoic 
acid and siaresinotannol, and about 10 per cent of an ester of benzoic 
acid and benzoresinol. Siabenzoresin on saponification yields 38 per cent 
benzoic acid, 57 per cent siaresinotannol, and 5 per cent of benzoresinol. 

Siam benzoin also contains .3 per cent of a benzoic ester, .15 to 1.5 per 
cent vanillin, a small quantity of free benzoic acid and 1 to 4 per cent of 
woody impurities. Dieterich states that cinnamic acid takes part in the 
composition of Siam as well as of Sumatra benzoin. This gum usually 
commands from four to five times the price of the Sumatra gum. 

Gum benzoin is produced under the stimulus of a wound in the tree, 
and cannot be a product of the bark. It is probably a pathological prod- 
uct of the injured protoplasm. 

The common adulterants of benzoin are, besides excessive amounts of 
wood and bark, colophony, turpentine, storax, dammar, and other resins. 
Reinitzer 1 states that Siamese benzoin first exudes as a milky wiiite 
body and does not contain the brown siaresinotannol described by Ludy 
as its principal constituent. The benzoin in loose tears is crystalline, 
melting 59°, and on heating to 40 to 50° in the dark it becomes darker and 
amorphous, probably owing to an oxidation process. The purified crys- 
tals melt 72.8°, and consist of the benzoate of an alcohol which Reinitzer 
terms lubanol. They give a green color with ferric chloride, and are cap- 
able of combining with a further quantity of benzoic acid. They give 
the Liebermann-Salkowski reaction and a fine blue color on warming with 
chloral hydrate. 

Siamese benzoin also contains the benzoate of a body resembling Ludy's 
benzoresitannol, but containing more oxygen. It melts at 279° C, crys- 
1 Ges. dent. Naturforacher und Aerzto, Sept., 1909; J. S. C. I., 1909, 1148. 



704 



ORGANIC SUBSTANCES 



tallizes in large prismatic needles, and is dextrorotatory in alcoholic solu- 
tion. Remit zer calls it siaresinol. It gives a sodium salt sparingly soluble 
in alcohol. It is nob oxidized on heating to 50°, does not give a color 
with ferric chloride, but responds to the L-S reaction. 

Siamese benzoin also contains an amorphous benzoate which turns 
reddish brown at ordinary temperatures and yields two bodies to carbon 
bisulphide. When heated at 100° in alkaline solution it is converted to 
Ludy's siaresinotannol. 

Sumatra benzoin likewise exudes originally with a white color and 
the sumaresinotannol is a secondary oxidation product. 

K. Dieterich has devised an examination applicable to benzoins in the 
commercial condition. This includes the estimation of ash and of data 
termed, respectively, " indirect acid number," " cold-saponification num- 
ber/' and " ester number." The last value is derived from the first two. 
The procedures are as follows: The weighed portions should be taken 
from a comparatively large amount of the material that has been finely 
powdered and well mixed. 

Indirect Acid Number. — One gram is mixed in a flask with 10 mils 
of half -normal alcoholic alkali and 50 mils of 96 per cent alcohol. The 
mixture is allowed to stand exactly five minutes, and then titrated with 
half -normal sulphuric acid and phenolphthalein until the solution is yellow, 
and a fresh portion of the indicator does not turn red on being dropped 
into the liquid, and the sodium sulphate separates readily. The super- 
natant liquid must be yellow. The mils of alkali neutralized by the 
sample, multiplied by 28.08, gives the acid number. 

Cold-saponification Number. — One gram of the sample is placed in 
a glass-stoppered flask with 20 mils of half-normal alcoholic alkali and 
50 mils of light petroleum (sp. gr. .700). The flask, tightly closed, is 
allowed to stand for twenty-four hours at room temperature; after dilu- 
tion with alcohol, the liquid is titrated with half-normal sulphuric acid 
and phenolphthalein. The mils of alkali neutralized, multiplied by 28.08, 
gives the cold-saponification number. 

The ester number is the difference between the above data. 

Dieterich gives the following as the limits of values with pure samples 
of the different benzoins: 





Siam 


Sumatra 


Palambang 


Padang 


Penang 


Ash 


Per cent 

0.03-1.5 

140-170 

220-240 

50-75 

95 


Per cent 

0.0-1.5 

100-130 

180-230 

65-125 

70-80 


Per cent 

1.1-4.02 
113.4-130.9 
198-219.8 
84-91 

91 


Per cent 

1.07 
121.8-124.6 
201.6-205.8 

79.8-81.2 


Per cent 

0.38-0.77 


Ind. A-N 


121.8-137.2 


Cold S-N 


210-296.8 


E-N 

Sol. in 96 per 
cent alcohol.. 


87.5-91.7 
94 



ORGANIC ACIDS— AROMATIC SERIES 705 



Balsams of Peru and Tolu 

These drugs are so closely related chemically that both can be considered 
simultaneously. 

The botanical source of Peru balsam has been the subject of some 
misunderstanding, and whether the species assigned to it has been confused 
with that of Tolu is a question for further study. 

Peru is, according to the Pharmacopoeia, a product of the Toluifera 
or Myroxilon periera (Leguminosae) . Kraemer describes the tree as grow- 
ing to the height of 50 feet and having a short trunk with branches appear- 
ing about 6 to 10 feet from the base. The leaves are compound and with 
seven to eleven alternate oblong, acuminate, glandular, punctate leaf- 
lets; the flowers are white and in simple axillary racemes; the fruit is a 
winged indehiscent one-seeded legume. The balsam is collected by mak- 
ing incisions in the bark and collecting it in gourds. The plant is found 
over the whole of Northern South America, extending through Central 
America into Mexico, and is cultivated in Singapore. 

A very fragrant vanilla-like balsam is obtained from the fruit of the 
same plant, and in San Salvador it is known as white Peru balsam to dis- 
tinguish it from the dark product obtained from the trunk. 

Dr. Albert Hale, 1 formerly of the Pan-American Union, has made a 
study of the interesting drug in its native heath, which he says is confined 
to a small area in the Republic of Salvador. 

This Balsam coast extends along the western Pacific slope of Salvador, 
between the ports of Acajutla and La Libert ad, a distance of only scant 
40 miles, or allowing a short distance on either side the extreme limits 
of the recognized growth of the tree in all this region is only 50 miles. 
Assuming that this strip has a depth from the coast of 15 miles, which 
is very liberal indeed, there is an area of only 750 square miles at the most 
over which the tree is exploited. Why nature restricts her activities so 
curiously as in this instance is an interesting problem for the botanist. 

The balsam tree is one of the most beautiful of a tropical forest. It 
may be found, in its natural state, in groups so evenly distributed as to 
suggest a plantation, but usually it grows rather isolated from its kind 
and even separated from its neighbors a respectful distance. In appear- 
ance it is a stout tree, measuring at full development about 1 meter (about 
40 inches) in diameter and reaching upward as tall as 25 to 35 meters (80 
to 115 feet). The trunk is cylindrical, the bark somewhat cracked, of 
a grayish or ashen color, with whitish blotches due to the parasitic lichen 
that cling to it. Few branches spring from it until the spread is reached, 
but the robust roots, especially in mature trees, extend along the surface 

1 Bull. Pan-Amer. Union, Vol. 22, 1911, 880. 



706 ORGANIC SUBSTANCES 

of the ground before sinking finally beneath the soil. The bark of the 
branches and twigs is also gray or reddish and covered with numerous little 
white and hard excrescent-like spots. The outer wood is white, the inner 
is red or almost black, and extraordinarily hard ; as it is also very durable 
it offers splendid material for construction work and furniture. 

Flowering takes place through a stem of about 10 centimeters (4 inches) 
long, with numerous white blossoms. The fruit is a pale yellow, mem- 
branous, feathery pod, with only one seed, as a rule. 

The life of the balsam tree is about one hundred years. The gathering 
of the sap is begun at the age of twenty-five years and may be continued 
indefinitely unless some accident to the tree occurs meanwhile. 

A well-nourished balsam tree will yield on the average from 3 to 4 
pounds of sap a year; the best of them, if cared for in anything like a 
modern agricultural system, can part with 8 pounds a year and still remain 
uninjured for the next seasom. 

Only the inner bark yields pure balsam, and then only from the mature 
tree; although the immature tree does give juice, it is nevertheless thin, 
light, poor in quality, and of small commercial value. 

This report from a man who has been on the ground certainly must 
be regarded in the light of authority. 

Tolu comes from Toluifera or Myroxilon balsamum, a tree which, 
according to Kraemer, reaches the height of 75 to 80 feet and whose 
branches appear at a height of 50 to 60 feet. Otherwise its description 
is the same as T. pereira. It grows in Northern South America. 

T. pernifera growing in Northeastern South America yields a balsam 
rimilar to Tolu. 

It would seem as if Kraemer's description of the Tolu balsam tree more 
nearly corresponded with the tree which Hale found yielding Peru balsam. 

Adulterants. — Peru balsam may contain Tolu balsam and storax, 
copaiba and gurjun balsams, turpentine, colophony, benzoin, castor oil. 
Owing to the rigid inspection during the last few years the grosser adulter- 
ation has ceased, but there exist in the market certain so-called " artificial " 
or " synthetic " Peru balsams, made from storax, Tolu and other sub- 
stances with probably a little Peru. 

Tolu balsam is relatively cheap and is not as liable to adulteration 
as is Peru. Colophony is the principal adulterant. 

Peru is a warm stimulating stomachic and expectorant and emollient. 
It is used in chronic catarrh, asthma, phthisis, and pectoral complaints 
generally, and also in gonorrhea, leucorrhea, amenorrhea, chronic rheuma- 
tism, and palsy. Locally it is employed for ulcers, running sores, skin 
affections, and blood poisoning. 

Combined with benzoin, tolu, etc., it is one of the constituents of 
Friar's balsam and other balsams and " baumes." It is dispensed in 



ORGANIC ACIDS— AROMATIC SERIES 707 

syrups and with mucilage of acacia and mixed with lead plaster it is used 
as a remedy for blood poisoning, wounds, and other skin affections. 

Tolu balsam has the same medicinal properties as Peru and will be 
found in the same class of compounds. Its greatest fame, however, is 
as a stimulant to the bronchial mucous membrane, and it occurs in the 
formulas of many mixtures recommended for coughs and colds. 

Syrup of Tolu is official in the Pharmacopoeia; liquid mixtures contain 
Tolu together with opium, ammonium chloride, licorice, wild cherry, and 
aromatics in syrupy form. Inhalants contain Tolu, iodin, phenol, gly- 
cerin, camphor, and cubebs. 

Bronchial tablets are composed of Tolu with ammonium chloride, 
licorice, cubeb, Hyoscyamus, senega, and ipecac, sometimes with opium; 
and other formulas include Tolu with licorice, cubeb, and sassafras; with 
coltsfoot, licorice, peppermint, Capsicum, and anise. Throat pastiles are 
composed of mixtures of some or all of the following: Tolu, coltsfoot, 
licorice, sugar, acacia, horehound, wild cherry, anise, cubeb, and Capsicum. 

Peru is a viscid balsam like syrup, honey, or molasses, of a dark red- 
dish-brown color, a fragrant vanilla-like odor, and a warm bitterish taste, 
leaving when swallowed a burning or prickling sensation in the throat. 
It does not harden on exposure. 

Tolu has at first a soft tenaceous consistency which varies considerably 
with the temperature. By age it becomes brittle and hard like rosin. 
It is shining, translucent, of a reddish or yellowish-brown color, a highly 
fragrant odor and a warm, somewhat sweetish and pungent, but not dis- 
agreeable taste. 

Allen tersely summarizes these drugs as follows : 

The cinnamic balsams are closely allied, consisting essentially of the 
benzyl and cinnamyl esters of benzoic and cinnamic acids, mixed with 
resinous oxidation products of these esters, free benzoic and cinnamic 
acids, and the Irydrocarbon cinnamene. The leading or characteristic 
constituents of Peru balsam may be said to be the cinnamein or benzyl 
cinnamate and styracin or cinnamyl cinnamate. Free benzyl alcohol is 
also present. In Tolu balsam, on the other hand, the proportion of resin 
is large; but of the esters benzyl benzoate predominates, and cinnamyl 
benzoate and cinnamate exist in but small proportions. In liquid storax 
of Mexican origin, phenylpropyl cinnamate exists in considerable quantity 
together with two isomeric alcohol-like substances called a and storesinol, 
to which the formula C3 6 H 5 5(OH)3 is attributed, and the cinnamic esters 
of these substances. 

In some cases the substances obtained from the cinnamic balsams 
have been decomposition products of the methods of analysis. The 
following method may be adopted for the recognition of the principal 
constituents of aromatic balsams: The substance is dissolved in 2 or 3 



708 ORGANIC SUBSTANCES 

parts of ether, and filtered from any insoluble matter. The solution is 
agitated with an equal volume of normal sodium hydroxide, the alkaline 
liquid withdrawn, and the agitation repeated with a fresh quantity of 
solution. If desired, the total acidity of the balsam can be deduced from 
the titration of an aliquot part of the alkaline liquid. The ethereal layer 
is then washed with water, and distilled at a gentle heat, the residue of 
neutral ester, etc., being weighed. The residue is then fractionally dis- 
tilled. 

The first fraction will contain any cinnamene which may be present, 
the next being rich in benzyl alcohol, which may be extracted by agitation 
with water and will yield benzaldehyde and benzoic acid by oxidation. 
Cinnamyl alcohol and benzyl benzoate pass over next, and at the higher 
temperature benzyl cinnamate and cinnamyl benzoate and cinnamate may 
be obtained. These esters suffer more or less decomposition unless the 
distillation is conducted in vacuo, and hence the last fraction consists 
largely of cinnamic acid, which can be removed by agitating the distillate 
with sodium carbonate solution. The alkaline liquid separated from the 
ethereal solution should be saturated with carbon dioxide, which precipi- 
tates much resin. The liquid is filtered, concentrated, and treated with 
hydrochloric acid, when a bulky precipitate is obtained representing the 
free benzoic and cinnamic acids of the balsam. These substances may 
be identified by their ordinary reactions. For their approximate separa- 
tion, one-half of the precipitate may be boiled with milk of lime and the 
liquid filtered and allowed to become cold, when the sparingly soluble 
calcium cinnamate is deposited in shining needles, the more soluble ben- 
zoate remaining in solution. When an exact estimation of the free acids 
of a balsam is desired, it is better to agitate the ethereal solution with 
sodium carbonate instead of sodium hydroxide, as the latter reagent is 
liable to cause some decomposition of the esters. 

Methods for the Examination of the Peru and Tolu. — Direct Acid 
Number. — One gram of the sample is dissolved in 200 mils of alcohol 
(96 per cent) and titrated with decmormal alcoholic alkali, using phenol- 
phthalein. The mils of alkali required multiplied by 5.616 gives the direct 
acid number. 

Cold Saponification Number. — The procedure is mainly as given under 
" Benzoin," using 1 gram of the sample in a 500-mil glass-stoppered flask 
with 50 mils of light petroleum (sp. gr. .700) and 50 mils N/2 alcoholic 
alkali. After standing twenty-four hours at room temperature, 300 mils 
of water is added, well shaken, until the separated dark alkali salt has been 
dissolved, and the solution titrated, with continuous agitation, with N/2 
sulphuric acid in the presence of phenolphthalein. The mils of alkali 
neutralized by the sample, multiplied by 28.08, gives the cold saponifica- 
tion number. 



ORGANIC ACIDS— AROMATIC SERIES 709 

The ester number is obtained by subtracting the direct acid number 
from the cold saponification number. 

Ether Insoluble Matter. — This is obtained by Dieterich by adding 
warm ether in small portions to a weighed portion of the sample until 
a portion of the solvent no longer leaves any residue on evaporation. The 
undissolved portion is then weighed. It will probably be better to extract 
in a Soxhlet tube. 

Aromatic and Volatile Ingredients. — The ethereal extract is shaken 
with 20 mils of a 2 per cent sodium hydroxide solution, separated and 
evaporated at room temperature until no odor of ether is perceptible. 
The residue is placed for twelve hours in the desiccator, weighed, placed 
for a second twelve hours in the same and weighed again. The mean 
between these two weights is taken as the datum for fixed matter from 
which the volatile matter can be calculated. 

Esters of Resin-acids. — The alkaline solution separated from ether by 
the action of the alkali, as noted in the last paragraph, is rendered acid 
by dilute hydrochloric acid, filtered through a tared filter and washed 
by the aid of a filter pump with as little water as possible until the wash- 
ings are free from chlorides. The residue dried at 80° to constant weight 
is taken. 

With these processes, Dieterich obtained from commercial samples 
of Peru Balsam the following range of data: 

Sp.gr : 1.135 1.145 

Direct acid number 60.0 80.0 

Cold saponification number 240 . 270 . 

Ester number 180.0 200.0 

Resin esters 20.0% 28.0% 

Aromatic and volatile ingredients 60.0% 77.0% 

Ether insoluble 1.5% 4.5% 

From authentic pure specimens from Honduras the following figures 
were obtained. 

/ II III 

Direct acid number 77.4 76.9 77.3 

Cold saponification number 241.0 214.3 215.0 

Ester number 165.6 137.4 137.6 

Resin esters 15.7% 13.2% 17.3% 

Aromatic and volatile ingredients . . 71.4% 77.5% 73.6% 

Ether insoluble 4.4% 4.3% 3.5% 

The United States Pharmacopoeia requires that Peru balsam shall 
have a sp. gr. between 1.130 and 1.160 at 25°, that when mixed with sodium 
hydroxide solution, one extraction with ether shall remove 50 to 56 per 
cent of cinnamein, and that the latter shall have a saponification value 
of from 235 to 238. According to the same authority, Peru balsam must 



710 ORGANIC SUBSTANCES 

have an acid value not less than 50 nor more than 84. The German 
Pharmacopoeia regulation is satisfied if the 56 per cent of cinnamein is 
obtained by three successive extractions with ether, but it must require 
at least 23.66 per cent of potassium hydroxide for hydrolysis, and the 
balsam must have a cold saponification value not less than 224.6. 

The acid number of Tolu balsam according to the U. S. P. should 
be not less than 112 nor more than 168, and the saponification value not 
less than 154 nor more than 220. 

The U. S. P. method for determining these figures is as follows: 

Dissolve about 1 gram of the Balsam, accurately weighed, in 50 mils 
of alcohol, add 1 mil of phenolphthalein T. S. and titrate the solution with 
half -normal alcoholic potassium hydroxide V. S. The acid number thus 
obtained is not less than 112 nor more than 168. Now add sufficient half- 
normal alcoholic potassium hydroxide V. S. to the neutralized liquid to 
make the total amount of the volumetric alkali solution exactly 20 mils; 
heat the liquid on a water-bath for half an hour, under a reflux condenser, 
and allow it to cool. Mix this liquid with 200 mils of distilled water, or 
more if necessary, and titrate the excess of potassium hydroxide with 
N/.5 sulphuric acid V. S.; the total amount of N/.5 potassium hydroxide 
V. S. consumed corresponds to a saponification value of not less than 
154 nor more than 220. 

The detection of rosin in Peru balsam may be effected by dissolving 
the balsam in ether and shaking the solution with sodium hydroxide which 
will dissolve out the acid constituents of the resin including any abietic 
acid. The alkaline liquid is then drawn off into another separator, acidi- 
fied, and shaken with ether, the ether evaporated and the residue of mixed 
acids washed several times with boiling water to remove the cinnamic 
and benzoic acids, and then subjected to the test for abietic acid. This 
acid dissolves in chloroform and on adding a drop or two of acetic anhy- 
dride followed by a drop of concentrated sulphuric acid a purple color 
changing to blue is obtained. 

Perrot and Goris detect rosin in Tolu by shaking 5 grams with 30 mils 
of carbon bisulphide in the cold or with gentle warming. The solvent is 
decanted and evaporated, the residue treated with 10 mils of light petro- 
leum ether, filtered and shaken with a 1-1000 solution of copper acetate. 
The presence of rosin is indicated by the appearance of a green color. 
The authors state the reaction is not applicable to Peru balsam as the 
pure drug gives a green color. This assertion may be correct, but it is 
also possible that at the time the researches were in progress the Peru 
balsams all contained rosin. 

Hartwich and Jama 1 from a study of the situation conclude that the 
balsams all come from the same tree, but of distant botanical varieties: 
1 Schweiz. woch. Chem., Pharm. 1909, 47, 625 and 841; J. S. C. 1 , 1901,1271. 



ORGANIC ACIDS— AROMATIC SERIES 



711 



Tolu from Myroxylon balsamum (L) var a-genuinum (Baill) . 
Peru from Myroxylon balsamum var perier3e (Baill) . 
Quino-quino Myroxylon balsamum var J. punctatum (Baill). 
They tabulate the analysis of these bodies as follows : 



Saponification No. 


Cinnamein 


Saponification No. of 
Cinnamein 


257.4 


65 


236 


255.5 


65.5 


243.5 


261.3 


65.9 


243.6 


263.7 


62.4 


262 


265 


61 


264 


255.3 


60.8 


265 


272.1 


57 


271 


269.3 


60 


265 



A sample labeled " synthetic " gave: 

Saponification No. 263.7, cinnamein 62.5 per cent, saponification No. 
of cinnamein 244. 

Heiduschka and Rheinberger r record the results of some observations 
made with a bromination test upon Peru balsam containing various admix- 
tures. A flask is fitted with a two-hole cork containing a pipette graduated 
to hold 1 mil of bromin and a thermometer; 20 mils of the solution of 
10 grams balsam in 100 mils chloroform are introduced into a flask 
and when the thermometer has attained the temperature of the mixture 
the bromin is added and the temperature noted after lj minutes. The 
pure balsam showed a value of 17°. 



Drug 



Tolu 

Castor Oil 

Storax 

Copaiba 

Turpentine 

Venice Turpentine 

Resin 

Santal OH 

Gurjun Balsam . . . 
Benzoin 



Bromin value with o per 
cent admixture. Degrees 



Bromin value with 10 per 
cent admixture. Degrees 



17 


17 


17.75 


18.25 


17.85 


19 


18.00 


18.75 


18.75 


21.50 


18.75 


20.50 


19.00 


20.00 


19.50 


21.75 


19.75 


22.75 


r- 


18.25 



Jensen 2 records that cinnamein from reliable Peru showed iodin 
numbers of 23.8 and 25.5 against 1.5 from synthetic esters. Upon frac- 
1 Pharm. Centrh., 50, 220. 2 Pharm. J., 90, 210. 



712 ORGANIC SUBSTANCES 

tional distillation of cinnamein the first 30 per cent was optically active 
when derived from the true balsam, but inactive when derived from the 
synthetic. Benzylbenzoate boils approximately 320° (ordinary pressure), 
173° at 9 mm., sp. gr. 1.121, saponification number 264.1. Benzyl cinna- 
mate boils 360° approx. (ordinary pressure), 213-214° at 9 mm., sp. gr. 
1.098, saponification No. 235.3. 

Merck's Method of Determination of Acid and Saponification Value. — 
One gram balsam is dissolved in 50 mils alcohol, 6 mils N/2 potassium 
hydroxide added, a few drops of phenolphthalein and after shaking, 200- 
300 mils water; the excess of alkali is titrated with N/2 hydrochloric acid 
and the volume of alkali used up by the balsam X 28 gives the acid value. 

The saponification value is determined by dissolving 1 gram balsam 
in 50 mils alcohol, adding 20 mils N/2 alcoholic potash, heating one-half 
hour over the steam-bath, adding 200 to 300 mils water and titrating 
with N/2 hydrochloric acid. The volume of alkali consumed by the saponi- 
fication X28 gives the saponification value. 

A method for determining " cinnamein " in aromatic balsams has been 
described by Lehmann and Muller. 1 A mixture of 2.5 grams of the balsam 
and 5 mils water is shaken for one minute with 30 mils ether in a 75-mil 
separator, 5 mils sodium hydroxide solution are added, shaken one minute 
and allowed to stand ten minutes ; the aqueous solution run off until about 
3 mils are left. After the addition of .5 gram tragacanth, the separator 
is shaken for three to five minutes and the ether poured off or filtered 
into a tared flask, evaporated and weighed. 

Delpin's 2 method of testing balsams in order to differentiate between 
the acid and resin esters is as follows: 

Balsam is dissolved in ether and shaken with N/1 sodium hydroxide, 
followed by 10 mils water. The ether is then evaporated and residue 
weighed as cinnamein. The alkaline solution is treated with 2 grams 
sodium bicarbonate and a stream of carbon dioxide slowly driven through 
the mixture for an hour, the solution filtered through a tared Gooch and 
the precipitate washed with warm water until the washings are no longer 
alkaline, the filtrate and washings being reserved. The precipitate on 
the Gooch is dried and weighed as resin ester. The alkaline solution is 
then treated with excess of hydrochloric acid, and the precipitated acids 
collected on a tared Gooch, washed with boiling water, dried and weighed 
as resin acids. The acid filtrate and washings are then shaken out with 
ether, and the cinnamic acid determined gravimetrically by drying in 
vacuo or by titrating in alcoholic solution. 

i Arch. Pharm., 1912, 250, 1. 

2 Svensk. Farm. Tidshr., 1907, 3, 415. 



ORGANIC ACIDS— AROMATIC SERIES 713 



Honduras Balsam 

Tschirch and Werdmuiler, 1 from an examination of three samples of 
light balsam, report specific gravity 1.0886, 1.0905, 1.0884, average acid 
value 32.67, average saponification value 173.2, corresponding to a total 
amount of 45.66 per cent cinnamic acid and 8.6 per cent free acid. Its 
odor resembles storax. When shaken with sodium carbonate it yielded 
cinnamic acid and a resin ester which yielded cinnamic acid and hondu- 
roresinol, melting 166-167°. On boiling with strong potassium hy droxide 
a phytosterol-like substance separated on cooling. The alkaline solu- 
tion also yielded an amorphous substance called /3-honduroresin, melting 
300°, insoluble in hot alcoholic potash, alcohol, ether, acetone, or petroleum 
ether with no phytosterol reactions. The " cinnamein " remaining after 
extracting the ether solution with alkali is a mixture of a hydrocarbon, 
CgHio, hondurane, boiling 154-155°, distyrene; another hydrocarbon, 
C9H12, boiling 140-155°; cinnamyl and phenyl-propyl cinnamates, and 
hondurol, C17H16O2, a dihydric unsaturated alcohol, melting 42.5°. 

Two dark samples gave an average acid value 29.9 and saponification 
value 153.9. They yielded products similar to the above. 

Tschirch and Werdmuller 2 have investigated Cabureiba balsam from 
Myrocarpus fastigiatus and M. frondosus from Peru, an aromatic balsam. 
It contains benzoic acid, vanillin, and a new resinotannol, but no cinnamic 
acid nor cinnamein. 

Patents have been obtained for soluble preparations of Peru balsam 
obtained by mixing the ingredients in the following proportions : 100 grams 
balsam with 50 grams glycerin, 50 grams 90 per cent alcohol and 50 mils 
potassium hydroxide solution 43° B., heating for several hours at 60° C. 
and running in gaseous formaldehyde, the process being continued until 
the product forms a clear solution with water. 



Storax 

Storax, styrax, or Oriental sweet gum, is obtained from the plant Liquid- 
ambar orientalis (Hamamelidaceae) . The tree grows profusely in the 
forests of Asia Minor, it is from 20 to 40 feet high. The leaves are 
palmate, the divisions obscurely three-lobed, serrate, smooth, bright 
green on upper and pale on under sufrace. 

Other species of Liquidambar yield a similar, if not an identical gum; 
L. styraciflua, the sweet-gum tree of this country exudes a storax used 
to some extent commercially and the resins from L. formosana and L. 
altingiana are of commercial importance. Storax is also obtained from 
the trees of the closely related genus Altingia. 

1 Arch. Pharm., 248, 420. 2 Aj C h. Pharm. 248, 431. 



714 ORGANIC SUBSTANCES 

At the present time our Pharmacopoeia recognizes only the resin of 
L. orient alis. 

It may be found adulterated with turpentine, colophony, castor or 
olive oils, labdanum, and cheap resins. 

It is used for the same purposes as Peru and Tolu balsams and may be 
found in the same class of formulas. 

Storax furnishes the aromatic component of some of the imitation 
Peru balsams. 

An extract of the bark of L. styraciflua furnishes a mucilaginous 
astringent which has been used in diarrhea and dysentery. 

Storax is a viscid, grayish, more or less opaque semiliquid mass, deposit- 
ing on standing a heavier dark brown, oleoresinous stratum; translucent 
in thin layers; odor agreeable, taste balsamic. 

It consists of about 50 per cent of two resin alcohols, a-storesin, and 
/3-storesin, which are partly free, partly in combination with cinnamic 
acid and partly with sodium, a-storesin (a-storesinol) is an amorphous 
substance that is very sparingly soluble in water and forms a crystalline 
compound with potassium. 

/3-storesin (/3-storesinol) occurs in white flakes somewhat soluble in 
water, and not forming a crystalline compound with potassium. Storax 
also contains from 10 to 20 per cent of an ester consisting of cinnamic 
acid and storesin; from 5 to 10 per cent of cinnamyl cinnamate; 10 per 
cent of phenylpropyl cinnamate, odorless and viscid; 2 to 3 per cent of 
phenylethylene (styrene) which occurs as a colorless liquid possessing the 
odor and pungent taste of the drug; from .5 to 1 per cent of a laevorota- 
tory volatile oil; 2 to 5 per cent of free cinnamic acid; about .15 per cent 
vanillin, and small quantities of benzoic acid, ethyl vanillin, resin, 
caoutchouc, and undetermined substances. It sometimes yields more 
than 20 per cent of free cinnamic acid. 

Burmese storax from Altingia excelsa is a soft white crystalline balsam 
developing the fragrant odor of styrene, and contains about 50 per cent 
of cinnamic esters. A brown solid balsam is also obtained from the same 
tree having a cinnamein-like odor, and containing a trace of free cinnamic 
acid and about 10 per cent of cinnamic esters. 

The examination of storax should in general follow the lines indicated 
under the other balsams and the same directions may be followed. 

Tschirch and van Itallie 1 have examined storax from L. orient alis 
and find free cinnamic acid, vanillin, stryol, styracin, ethyl cinnamate, 
and storesinol partly free and partly as ester. No benzoic acid was 
detected. Storesinol is a white, odorless powder, melting 156-161°, 
C16H26O2, insoluble in light petroleum ether, but dissolves in other organic 
solvents and in alkalies. It is isomeric with benzoresinols but with a 

1 Arch. Pharm., 239, 506. 



ORGANIC ACIDS— AROMATIC SERIES 715 

lower melting-point. It forms crystalline compounds with potassium 
hydroxide, separating in acicular crystals. It yields acetic and salicylic 
acid on alkaline fusion. On distillation with zinc dust it yields, phenol, 
toluene, and benzene. It does not acetylate nor give a benzoyl compound, 
nor any derivative with hydroxylaixiin nor phenyl hydrazine. Oxidized 
with nitric acid it gave picric and oxalic acids. 

The same authors 1 working on American storax say that the con- 
stitutents are much the same, consisting of cinnamic acid, vanillin, styrol, 
styracin, cinnamic phenyl propyl ether, and styresinol partly free and 
partly in form of cinnamic ester. No ethyl cinnamate was detected. 
Styresinol is apparently an isomeride of storesinol having the same 
formula and melting-point but differing in optical activity, its specific 
rotation being +13° 19' as compared with +52° for storesinol. In all 
other respects the resins are identical. 

Determination of Total Cinnamic Acid. — The sample is saponified 
with excess of alcoholic potash, the alcohol evaporated, the residue dis- 
solved in water, transferred to a separator, washed with 10 mils ether and 
the ether rejected. An excess of dilute sulphuric acid is added and the 
liberated acids shaken out with 3 portions of ether. The ether is collected 
in a flask, evaporated, and the residue boiled with 50-100 mils of water 
under a reflux; the water filtered off while hot into another separator; 
and the extraction with boiling water repeated twice. The combined 
aqueous solutions when cool are then shaken out three times with ether, 
the solvent filtered and evaporated and the residue dried in vacuo or 
titrated. 

Umney records the analyses of samples of storax imported from 1907- 
1911 in which the acid values rose from 68 to 111, the ester values fell 
from 112 to as low as 14 in individual cases, but averaged in the last 60- 
70, and the cinnamic acid free and combined fell from 19 per cent to 2.5 
per cent. He also worked on two samples which Professor Greenish had 
kept for eleven years, the crude resin showing acid values 50.6, ester 
value 100.4, total cinnamic acid 20.6 per cent. This sample yielded a 
purified storax with acid value 60.1, ester value 130.1 and total cinnamic 
acid 25.5 per cent. 

Purified storax is prepared by dissolving the resin in alcohol, separating 
from the insoluble portion and removing the solvent. It is a brownish- 
yellow viscous balsam, transparent in thin layers, with an agreeable odor 
and balsamic taste, entirely soluble in alcohol and ether. When heated 
on a water-bath it should lose not more than 5 per cent. The acid value 
should range between 60 to 90 and the ester value 110 to 140. 

Storax adulterated with rosin yields to petroleum ether from 55 to 
65 per cent, the extract having an acid value 116 to 121, and saponifica- 

*Arch. Pharm., 239, 532. 



716 



ORGANIC SUBSTANCES 



tion value (cold) 171 to 177. Pure storax gives a 37 to 47 per cent extract 
with acid value 37 to 47 and saponification value (cold) 194 to 198. 



Nan-ta-yok or Burmese Storax 

Hooper * examined this balsam, which has long been used in Burma 
as incense and for medicinal purposes. It is produced by Altingia excelsa 
(Noronha), a large tree (150 to 180 feet high) growing in the forests of 
the Indian Archipelago, Burma, Assam, and Bhutoa, and especially in 
the Tenasserim province of Burma. It is also found in China, Java, 
Cochin China, New Guinea, and Sunda Archipelago. Three samples of 
resinous balsam from Java examined by Tschich and van Itallie were 
said to be the products of two species of Altingia, but in GreshofPs opinion 
both trees were Altingia excelsa. The two aromatic exudations from 
South Tenasserim examined by the author had the following properties : 

Soft White Crystalline Balsam. — This resembles honey when fresh, 
but after two years crystallized, and become white, and had a fragrant 
odor of styrol. It melted at 41° C, and when heated on the water-bath 
lost 7.65 per cent in weight, the volatile substances being chiefly essential 
oils. It gives the following values: Acid value, 24.96; saponification 
value, 199.35; and iodin value, 57.3. About hah the balsam consisted 
of an ester of cinnamic acid, the amount of the lattei separated being 37 
per cent calculated on the original balsam. 

Dark-brown Solid Balsam. — This consisted of resinous masses which 
yielded brown powder with an aromatic odor in which that of cinnamon 
predominated. After clarification with alcohol two samples gave the 
following results: Resins, 53.72 and 54.70; organic impurities 19.09 and 
28.05; inorganic impurities 22.24 and 10.67; and volatile oil and loss, 
4.95 and 6.58 per cent. The purified resin (m. pt. 68° C.) was clear, 
gave amber color, and had the fragrant odor of the crude balsam. It 
was soluble in chloroform, carbon bisulphide, and benzene, partially 
soluble in acetic ether, and slightly soluble in petroleum spirit. 





Acid Value 


Saponification 
Value 


Iodine Value 


Crude Resins 

Pure Resins 


52.48 
76.80 


130.10 
130 . 44 


41.07 
51.68 



The brown balsam contained a trace of free cinnamic acid, and 9.7 
per cent of that acid in the form of an ester. The author's conclusion is 
that the white balsam is valuable as a perfume and as a source of cinnamic 

1 Agri. Ledger, 1904, 115. 



ORGANIC ACIDS— AROMATIC SERIES 717 

acid, while the brown balsam is of value a-s a perfume and as incense. 
Both possess a sweeter aroma than genuine storax, and when heated with 
sulphuric acid and potassium bichromate, both evolve an odor of benzal- 
dehyde. If examined by Dieterich's method the brown resinous balsam 
cannot be regarded as true storax, while the white balsam only agrees 
with that resin in the saponification value. Hence the author's results 
confirm the statement of Tschirch and van Itallie that Nan-ta-yok resin 
differs in constitution from the genuine storax of Asia Minor. 

SULPHONIC ACIDS AND THEIR DERIVATIVES 

Sulphanilic acid, CeH^NH^jSOsK 

This acid, which is chemically amidobenzene-p-sulphonic acid, is pre- 
pared by heating anilin sulphate to 200° C. It crystallizes with 2H2O, 
readily soluble in hot, but sparingly in cold water, and insoluble in alcohol 
and ether; on heating to 280-300° it is decomposed. It forms salts with 
bases, but does not combine with acids, the basic character of the amido 
group being neutralized by the acid character of the sulphonic ; when fused 
with alkali it yields anilin. Chromic acid oxidizes it to quinone. When 
dissolved in dilute sodium hydroxide and mixed with a slight excess of 
sodium nitrite, and poured into cold dilute sulphuric acid, diazobenzene 
sulphonic acid is formed. 

/NHa /N : NOH 

C 6 H< +HOXO = C 6 Hi < +H 2 0, 

\S0 3 H X S0 3 H 

which compound immediately loses water and separates as the anhydride 

"NT • Ttf 
in colorless C6H4C 

X S0 3 

In medicine sulphanilic acid is used in Ehrlich's diazo reaction for 
typhoid urines, and is sometimes given for chronic catarrh. 

/S0 3 Xa 
Cosaprin, Sodium acid sulphanilate, CqEa\ is used as 

x XH(COCH3) 
an antipyretic. 

PHENOL SULPHONIC ACIDS 

Phenol-o-sulphonic acid, C6H4OHSO3H, is formed, together with a 
small quantity of the p-acid when a solution of phenol in concentrated 
sulphuric acid is kept for some time at ordinary temperatures. It has been 
stated that on heating to 100-120° the o-acid is gradually converted to 
the p-acid, but recent experiments indicate that this is erroneous. 



718 ORGANIC SUBSTANCES 

The o-acid known as ortho-sulphocarbolic or sozolic acid, is soluble in 
water, glycerin, and alcohol, but not in ether. It has a phenol-like odor 
and gives a violet color with ferric chloride. It is used extensively as an 
antiseptic. Aseptol, which is sold as a 33 per cent solution of the o-acid, 
really consists in large parts of the p-acid. 

Phenol-p-sulphonic acid is a powerful antiseptic and its sodium and 
zinc salts are official in the Pharmacopoeia. Solutions of this acid coagu- 
late albumin, and give a violet color with ferric chloride, but the phenol 
sulphonic acids are readily distinguished from salicylic acid as they are 
not removed from acid solution by ether or chloroform. On boiling a 
solution of the acid with an equal volume of concentrated nitric acid and 
neutralizing with potassium hydroxide, a yellow color due to picrate is 
produced. On adding bromin to a solution of the acid a precipitate of 
tribrom phenol is thrown down, and sulphuric acid is liberated in solution, 
recognizable by its insoluble barium precipitate. The acid, on heating to 
250° with potash, gives resorcinol. The potassium salt on fusion with 
potash yields catechol. 

When the sodium salt is ignited it leaves in part a residue of sodium 
sulphate. The zinc salt does not yield the sulphate unless sodium car- 
bonate is present. 

The aluminum salt is known as Sozal. It is soluble in water and used 
as a substitute for iodoform. 

Mercury phenol parasulphonate also called Hydrargyrol, is soluble 
in water and glycerin and insoluble in absolute alcohol. It is used as an 
antiseptic in place of mercuric chloride. 

The estimation of the acid may be accomplished by the nitric acid 
reaction, precipitating the sulphuric acid formed, by means of barium, 
and weighing the barium sulphate, or it may be done by the following 
bromin method: .2 to .3 gram of the acid or salt with .6 to 1 gram barium 
chloride are dissolved in 100 mils water containing 10 mils hydrochloric 
acid 1.19 sp. gr. The mixture is heated to 60 to 65° and slowly treated 
with a solution containing, 1 gram potassium bromate and 5 grams brom- 
ide in 100 mils, until a faint persistent yellow color is produced. A small 
quantity of an alcoholic solution of phenol is added to remove the excess 
of bromin and then sufficient alcohol to dissolve the tribrom phenol. 
The container is then boiled and the liquid decanted from the barium 
sulphate, which is repeatedly washed with 50 per cent alcohol, then with 
water and finally filtered and weighed. 

Ni'troparaphenol sulphonic acid in the form of a soluble salt with 
potassium and mercury known as Phenegol is a reddish-brown, odorless, 
tasteless powder, soluble in water and used as an antiseptic. Its composi- 
tion is given as CeHsCONC^SCfeK) : Hg : (KS0 3 N020)C 6 H5. 

Analogous to the phenolsulphonic acids are resorcinoldisulphonic acid, 



ORGANIC ACIDS— AROMATIC SERIES 719 

C 6 H2(OH)2(S0 3 H)2, and thymol sulphonic acid, Ci H 12 OHSO 3 H, both 
soluble in water and alcohol, the former decomposing above 100° and the 
latter melting at 91-92°. 

Diiodoparaphenol sulphonic, sozioclolic acid or soziodol, C6H2i2(OH) 
SO3H, is a white crystalline powder, slightly soluble in cold water, readily 
in alcohol and glycerin, decomposed on heating to 200° with evolution of 
iodin. It gives a violet color with ferric chloride and a white precipitate 
with silver nitrate soluble in nitric acid. Its salts are used to some extent 
in medicine, especially those of mercury, sodium, potassium, zinc, and 
magnesium. They are antiseptic and antipyretic. 

Ichthyol Compounds 

On distilling certain bituminous shales an oily product known as crude 
ichthyol oil is obtained. This raw product on treatment with concen- 
trated sulphuric acid yields a sulphonated product, probably a mixture of 
sulphonated hydrocarbons, and other sulphonated products with a variety 
of undertermined substances. On neutralizing the sulphonated acids with 
ammonia and evaporating to a thick syrup, the product known commer- 
cially as ichthyol or ammonium ichthyol sulphate is obtained. There 
are a number of other ichthyol compounds and they are all used for anti- 
septic purposes, owing their efficiency probably to the sulphonic bodies 
contained therein. They are recommended also as antiphlogistics, 
anodynes, and alteratives and are dispensed for internal and external 
use. They are often found in ointments, suppositories, and bougies, in 
remedies for ivy poisoning and in mixtures for uterine ailments combined 
with iodin, boric acid, Hydrastis, glycerin, and phenol. 

There are a number of imitations of the natural product on the market, 
but whether they are any less effective than the genuine is still a matter 
for physiological research. 

The sulphur in the product made from the natural distillate is present 
in three forms, first the combined sulphur naturally occurring in the dis- 
tillate, second, the sulphur introduced by sulphonating and third, that 
in the form of sulphate. 

Both of the ammonium and sodium compounds are brown syrupy 
liquids with a bituminous odor and taste. Water or a mixture of alcohol 
and ether dissolves the liquid, and pure alcohol or ether takes it up in 
part. Hydrochloric acid precipitates a resinous mass which is soluble 
in ether. The ammonium compound gives off ammonia on warming with 
caustic alkalies. The compounds of lithium, zinc, mercury, and silver 
have been prepared and are used as drugs. 

The reactions and tests for ichthyol (the ammonium compound) may 
be briefly stated as follows : 



720 ORGANIC SUBSTANCES 

The aqueous solution (1:10) has a faintly acid reaction upon blue 
litmus paper, and yields a greenish-black, resin-like precipitate upon the 
addition of hydrochloric acid. This precipitate is partially soluble in 
ether and alcohol; soluble in water, but if dissolved in the latter solvent 
it may again be precipitated from solution by the addition of hydrochloric 
acid. 

With barium chloride test solution it gives a brownish-black precipi- 
tate which is soluble in dilute hydrochloric acid. 

Ichthyol is incompatible with acid and saline solutions, fixed alkalies, 
their carbonates and iodides, alkaloidal salts, and mercuric chloride. 

If dried at 100° C. ichthyol should not lose more than 47 per cent of 
its weight. 

If from 5 to 6 grams of ichthyol are weighed into a flask, 25 mils of 
potassium hydroxide test solution and 100 mils of water added, the 
mixture distilled until no more ammonia passes over, the distillate col- 
lected in 15 mils of normal sulphuric acid to which 1 drop of methyl red 
test solution has been added, and the excess of acid then titrated with 
N/10 potassium hydroxide, the amount of normal sulphuric acid con- 
sumed should correspond to from 2.9 to 3.4 per cent of total ammonia 
(NH 3 ). 

' If from 5 to 6 grams of ichthyol are weighed into a beaker, diluted with 
50 mils of water, 10 mils of a 10 per cent solution of albumin added, followed 
b}' 5 portions of 5 mils each of diluted hydrochloric acid, shaking after 
each addition, the mixture made up to a volume of 500 mils and filtered 
through a diy filter, and if 200 mils of the filtrate are heated to boiling, 
10 mils of barium chloride test solution added, the mixture allowed to 
stand for twenty-four hours, the precipitate of barium sulphate collected, 
heated and weighed in the usual way, the weight of barium sulphate 
obtained should correspond to from 5.7 to 6.2 per cent of ammonium 
sulphate. 

If from .5 to 1 gram of ichthyol is weighed into a Kjeldahl flask, 
diluted with 30 mils of water, 5 grams of potassium chlorate added, followed 
by 30 mils of nitric acid, the mixture evaporated to about 5 mils, 25 mils 
of hydrochloric acid again added, this solution evaporated to about 5 mils 
100 mils of water added, the solution heated to boiling, 10 mils of barium 
chloride rest solution added, the mixture allowed to stand for twenty- 
four hours, the precipitate of barium sulphate collected, heated, and 
weighed in the usual way, the weight of barium sulphate should corre- 
spond to at least 10 per cent of the total sulphur. 

If the ammonia contained in the ammonium sulphate as previously 
determined in ichthyol is calculated, and the result subtracted from the 
" total ammonia " as previously determined, the remainder should repre- 
sent the ammonia combined with the organic sulphonic acids. If this 



ORGANIC ACIDS— AROMATIC SERIES 721 

value is multiplied by 1.88 the result should represent the sulphur present 
in the sulphonic acids in an oxidized state, i.e., the " sulphonic sulphur." 

If the sulphur contained in the ammonium sulphate as previously 
determined in ichthyol is calculated, and the result subtracted from the 
" total sulphur " as previously determined, the remainder should repre- 
sent the sulphur present in the organic-sulphonic acids contained in the 
substance. 

If the " sulphonic " sulphur in icy thy ol as previously calculated is 
subtracted from the sulphur in the organic-sulphuric acids as previously 
calculated, the remainder should correspond to at least 5.5 per cent of 
" organic " (" sulphidic ") sulphur. 

Calcium Ichthyol is a derivative of ichthyol in which calcium is sub- 
stituted for ammonium. 

It is a brown, tasteless powder, insoluble in water, and containing 
2.5 per cent of calcium. 

Ichthalbin. — Ichthyol Albuminate is a compound of ichthyol-sulphonic 
acid and albumin analogous to tannalbumin. 

It is a extremely fine, grayish-white powder, odorless and practically 
tasteless, insoluble in water, in the gastric juice, or in acid liquids, but 
completely soluble in alkaline liquids. 

Ferrichthyol is a brown-black permanent powder, nearly odorless and 
tasteless, containing 2.5 per cent iron. It is insoluble in the ordinary 
solvents, acids or alkalies. 

Tumenol 

Tumenol is a mixture of sulphones and sulphonic acids obtained from 
bituminous minerals and in the crude form is a blackish-brown liquid 
soluble in ether. 

Tumenolsulphone is that portion of the crude mixture which is extracted 
by ether after saponification. It is used in antiseptic ointments. 

The acid products obtained from the crude oil are solid and easily 
soluble in water. 

These materials are all used as antiseptics in skin diseases. 

BILE ACIDS 

Oxgall or bile both in its original condition and in a purified state is 
recognized by the U. S. Pharmacopoeia, and as a remedy is employed in 
gallstones, constipation, catarrhal jaundice, and other conditions of a 
diseased liver. The purified bile of the hog and other animals is also 
used medicinally. It is probable that the efficiency of these secretions 



722 ORGANIC SUBSTANCES 

is due, at least in part, to the animal acids which they contain. These 
acids have been separated in a condition of greater or less purity and sold 
under various proprietary names for diseased conditions. 

Inspissated oxgall is prepared by straining fresh bile and evaporating 
to the consistency of a solid extract. 

Oxgall is combined with other chemicals in various mixtures intended 
as tonics for convalescents and for ansemics and consumptives. It will 
be found in admixture with hypophosphites in liquid preparations, with 
modified or so-called " metabolized " oils and with extracts of other 
animal secretions, spleen, testicles, etc. 

The purified bile is dispensed alone in pill, tablet, and capsule form. 
Some of the combinations include ginger, colocynth, pancreatin, pepsin, 
Nux Vomica; also shotgun prescriptions of some or all of them together 
and with perhaps the further addition of aloes, berberin, stramonium, 
quinin, and Taraxacum. 

Comparatively recent investigations have elucidated the composition 
of bile and demonstrated the presence of complex nitrogenous and nitro- 
genous sulphur acids. Some of these acids have been separated in a fair 
condition of purity, and a number of products have appeared on the 
market, the activity of which is credited to these acids. Glycocholic, 
C26H43O6N, and taurocholic acids, C25H45O7NS, occur in oxbile in the 
form of their sodium salts. They may be separated in the following 
manner. Dry oxbile is treated with absolute alcohol and the tincture 
precipitated by ether in excess. Both salts are deposited and the glyco- 
cholate crystallizes upon standing, the taurocholate remaining in amor- 
phous form, resembling oily or resinous matter. If the deposit is dis- 
solved in water, solution of lead acetate will throw down a lead glyco- 
cholate, while the addition of lead subacetate to the remainder will pre- 
cipitate the taurocholate. 

All the bile acids respond to Pettenkofer's test. A small portion of 
the salt is dissolved in a little concentrated sulphuric acid in a small por- 
celain dish and warmed, care being taken that the temperature does not 
rise higher than 60° to 70° C. A 10 per cent solution of cane sugar is 
then added drop by drop while the liquid is stirred with a glass rod. If 
compounds of cholic acid are present a beautiful red color will appear, 
which does not disappear at room temperature, but usually in the course 
of a day becomes bluish violet. The red liquid shows in the spectrum 
two absorption bands, one at F and the other between D and E near to 
E. Care must be taken not to heat too much nor to add too much sugar. 
The sulphuric acid must be free from sulphurous acid and the lower oxides 
of nitrogen. As albumin, oleic acid, amyl alcohol, morphin, etc., may give 
a similar reaction, spectroscopic examination should not be omitted in 
doubtful cases. 



ORGANIC ACIDS— AROMATIC SERIES 723 

Furfurol Test (Myllus): The substance is dissolved in alcohol and 
for every mil of the alcoholic solution, one drop of a 1 : 1000 furfurol 
solution and one mil of concentrated sulphuric acid are added and the 
mixture cooled, if necessary, so that the temperature may not rise too 
high. The same color reaction occurs as in PettenkofTer's test. 

Both glycocholic and taurocholic acids generally undergo hydrolysis 
under the influence of dilute acids or alkalies. The former yields cholalic 
acid, C24H40O5, and glycocoll, C2H5O2N, and the latter cholalic acid and 
taurine, C2H7O3NS. 

Glycocholic acid, C23H39O3 • CO • NH • CH2COOH, forms glistening 
scales or needles which vary in melting-point from 132-152°, depending 
on the mode of preparation. It is slightly soluble in hot water and ether, 
readily soluble in alcohol and insoluble in chloroform and benzole. 

Taurocholic acid, C22H39O3CONH.CH2CH2— S0 2 OH, forms hygro- 
scopic silky needles, readily soluble in alcohol and water, insoluble in 
ether, benzol, and acetone. When heated, it contracts at 140° and begins 
to break up at 160°, forming a liquid at 180°. Its solution in water has 
the property of holding up glycocholic acid. 

Both acids are dextrorotatory. The amount of taurocholic acid may 
be estimated by calculation from the amount of sulphur contained in an 
alcoholic solution of the bile. 

/COOH 

Cholalic or cholic acid, C2oH3i^(CH-OH)o, crystallizes in the form of 

\CHOH 

rhombic plates or prisms with one molecule of water, or from alcohol in 
rhombic tetra- or octahedra with one molecule of the solvent. The crys- 
tals are very sparingly soluble in water and ether, but dissolve readily in 
alcohol. The alcohol molecule may be driven off by heating between 
100-120°, and the acid melts 195°. The acid gives a blue compound 
with iodin. When added to 25 per cent hydrochloric acid at the ordinary 
temperature, a violet-blue color gradually develops, changing slowly to 
green and yellow. The blue solution shows an absorption band at D. 

Glycocholeic acid, C27H45O5N, and taurocholeic, C27H47O6NS, occur 
in bile. Hyoglycocholic acid, C27H43O5N, is obtained from pig's bile. 
Cheno-taurocholic acid is the chief taurocholic acid of goose-bile. Hyo- 
cholic acid, C25H44O4, and chenocholic acid, C27H44O4, are obtained by 
the hydrolysis of the conjugated acids of the bile of the pig and goose 
respectively. 

Oxbile itself may be described as a brownish or dark-green, some- 
what viscid liquid having a peculiar unpleasant odor and a disagreeable 
bitter taste. It has a specific gravity of 1.015-1.025 at 25° and is neutral 
or faintly alkaline. A small quantity of an aqueous mixture when treated 
with a crystal of sugar which is allowed to dissolve and afterward with a 



724 ORGANIC SUBSTANCES 

drop or two of sulphuric acid cautiously added until the precipitate first 
found is redissolved will give a brownish color changing to carmine, 
purple, and violet. Attention should be directed to this reaction because 
it simulates that given by cod-liver oil and sulphuric acid, and both cod- 
liver oil or cod-liver extracts are dispensed with oxgall. 

Purified oxgall is virtually an alcoholic extract of bile. The albumin- 
oids present in the original secretion are mostly absent, but the bile acids, 
pigments, etc., are still present. It is completely soluble in water and 
alcohol and the aqueous solution is not precipitated by alcohol. 

The mixed salts of bile acids will be found on the market under various 
proprietary names, 

Colalin 

Colalin consists essentially of a mixture of hyoglycocholic and hyotauro- 
cholic acids, obtained from bile. To preserve the pulverulent condition 
a little magnesium carbonate is added. 

It is a yellow powder of faint odor and persistent bitter taste. It 
melts at 103 to 107° C, is slightly soluble in water, and acid toward litmus. 

Colalin should be readily soluble in alcohol and this solution should 
rotate polarized light to the right. It should dissolve almost entirely 
in a dilute solution of sodium carbonate with evolution of carbon dioxide 
and in a dilute solution of sodium hydroxide. The solution in sodium 
hydroxide should not be rendered turbid by the addition of barium 
hydroxide (absence of fatty acids). It should not contain more than a 
trace of sulphur (absence of taurin). 

This product which is usually sold in the form of tablets is recommended 
for the removal of gallstones, 

NUCLEIN, NUCLEIC ACID, AND NUCLEATES 

Nucleins are modified nucleoproteins obtained by peptic digestion or 
by treatment with dilute acids. They are split up by the action of alkalies 
or by tryptic digestion into a protein constituent and a nucleic acid vary- 
ing somewhat with the source of the nucleoprotein from which they are 
derived. The nucleic acids of commerce are apt to contain some protein 
in combination. They are most commonly made from yeast cells, but 
have been made, also, from the wheat embryo, the sperm of certain fishes 
and from the thymus and pancreas glands. In composition they approxi- 
mate the formula C40H52N14O25P4. From the wheat embryo products 
with relatively more nitrogen have been obtained. 

Nucleins are colorless, amorphous, insoluble in alcohol and ether and 
insoluble or slightly soluble in water. They are more or less readily dis- 



ORGANIC ACIDS— AROMATIC SERIES 725 

solved by dilute alkalies. They give the biuret test and Millon's reaction. 
They show a great affinity for many dyes, taking them up from aqueous 
or alcoholic solutions. The term nuclein is sometimes used to designate 
an impure nucleic acid, which usage has led to confusion, as the nucleic 
acids are bodies of definite composition. 

Both nucleins and nucleic acids yield metaphosphoric acid on inciner- 
ation. On fusion with potassium nitrate and sodium carbonate they 
yield alkali phosphates. 

Nuclein and nucleic acid and nucleates are said to increase the number 
of white corpuscles, and it has been claimed that this increases the resist- 
ance to infection. 

Nuclein and nucleic acid and nucleates have been used in tuberculosis 
and various infections. 

The crude nuclein is separated from the yeast by bringing into solu- 
tion the albuminous substances and nuclein by means of an alkali, pre- 
cipitating the albuminous substances by adding acetic acid and heating 
to 75°, filtering and precipitating the crude nuclein from the filtrate by 
acidulated alcohol. It is purified by dissolving in water or weak alkali, 
adding dilute potassium permanganate, filtering, and again precipitating 
with acidulated alcohol. 

Another process consists in acting on yeast in presence of water at a 
temperature of 70-75° with sodium zincate, aluminate or similar metallate, 
acidifying with acetic acid, filtering, heating, and throwing out the sodium 
nuclein compound with alcohol. From this salt the nuclein is obtained 
by dissolving it in a little water and pouring into alcoholic hydrochloric 
acid solution. 

Pure nucleic acid is a white amorphous powder with an acid reaction 
readily soluble in water containing a little alkali, insoluble in alcohol 
and ether. From its solutions in alkalies, it may be precipitated by 
hydrochloric acid, but not by acetic acid. When chemically pure it does 
not give the biuret test or Millon's reaction, but the commercial article 
often gives a slight response to these reactions. 

It should contain between 14.5 and 16.5 per cent nitrogen and between 
8.5 and 10.5 per cent of phosphorus. 

Nuclein is dispensed both in the solid condition and in capsules. The 
solutions usually contain about 5 per cent of nucleic acid. 

The metallic compounds of nuclein are prepared by adding solutions 
of the metals to an alkaline solution of the nuclein and precipitating the 
compound with alcohol. 

Cuprol is a copper compound containing about 6 per cent of the metal. 
It is a greenish powder soluble in water, and is used as an astringent alter- 
ative, its special field being in ophthalmic practice. 

Ferrinol, an iron nuclein compound, is a brown powder freely soluble 



726 ORGANIC SUBSTANCES 

in water, containing about 6 per cent of iron and 4.5 per cent phosphorus 
combined in the nuclein. It is employed as a tonic and reconstructive. 

Mercurol is a mercury compound, a colorless or brownish- white powder 
containing 10 per cent of mercury, soluble in water with a weak alkaline 
reaction. It is used internally and locally as a substitute for mercuric 
chloride and is recommended for syphilis. 

Nargol is the silver compound of this series. It is a gonorrhea remedy 
and is recommended as a local application in all forms of diseases for which 
silver nitrate has been used. It is a light brownish-white powder, soluble 
in water and contains 10 per cent of silver. 

Complex compounds of silver are prepared by treating the crude 
nuclein with formaldehyde and subsequently obtaining the silver com- 
pound by treating a soluble salt with silver nitrate which is dissolved in 
a solution of some neutral salt, and reprecipitated in a soluble form by 
alcohol. 



Sophol 

Sophol is a compound of silver and methylenenucleinic acid, the silver 
being in the organic (" masked ") form. 

It is a yellowish powder, having a metallic taste and claimed to con- 
tain silver, equivalent to not less than 20 per cent metallic silver. It is 
readily soluble in water, the aqueous solution having a faint alkaline 
reaction; it does not give a precipitate on the addition of dilute solution 
of sodium hydroxide or of sodium chloride; it is insoluble in ether and 
alcohol. 

If .5 gram sophol is boiled with 5 mils of sodium hydroxide solution, 
the latter assumes a black color with the development of a formaldehyde 
odor. 



CHAPTER XIX 

ETHEREAL SALTS— PHENOLS 

ETHEREAL SALTS 

The alcohols combine with organic and inorganic acids to form a 
large class of substances known as ethereal salts or esters. Many of these 
bodies are of great importance in medicine. Some of them, like the 
ethereal salts of the halogen acids, are identical with the monohalogen 
substitution products of the hydrocarbons. The di-, tri- and higher sub- 
stitution products of the paraffins such as chloroform, CHCI3, are not 
strictly ethereal salts, but their analogy and relationship is so close that 
they are conveniently considered under this heading. 

We shall not undertake a description of all of these bodies, but will 
treat in full only those of interest to our work. 

The ethereal salts are in general neutral in reaction, unless in excep- 
tional cases only they may contain a free carboxyl or phenolic hydroxyl 
group. They are removable from acid or alkaline mixtures with immiscible 
solvents, and are hydrolyzed into 'their components by saponification 
with alcoholic potash. From the alkaline mixture the alcoholic portion 
can be separated by distillation or by shaking out with ether, and then on 
adding sulphuric acid, the acid constituent is freed, and may be recognized 
by appropriate tests, 

Methyl Chloride 

Methyl chloride, CH3CI, is the hydrochloric acid ester of methyl 
alcohol. It occurs, in the condensed state, as a colorless liquid, having 
an ethereal odor, and a sweet taste. 

Methyl chloride is insoluble in water, more readily in alcohol, freely 
in ether and chloroform, and also in acetic acid. At about -25° C. it 
has a specific gravity of .991, and boils at about —21° C. It burns in 
air with a greenish flame, though it is not highly inflammable. The 
neutral solution is not precipitated by solution of silver nitrate, nor is 
there any reaction with potassium iodide and starch paste. In the liquid 
condition, it is a powerful refrigerating agent. At very low temperatures 
it forms with water a hydrate, CH 3 C1-9H20. 

727 



728 ORGANIC SUBSTANCES 

It is used as a general anesthetic mixed with ethyl chloride and ethyl 
bromide. 

Methyl Iodide, CHJ 

Methyl iodide or iodomethane is a colorless, transparent liquid, which 
turns brown on exposure to the light. It boils 42° C, specific gravity 
2.279 at 15° C. It is used as a vesicant and sometimes replaces cantha- 
rides in blistering compounds. 

Methyl Acetylsalicylate, C 6 H 4 (COCH 3 )OCOCH 3 

This ester, known also as methyl rhodin and methyl aspirin, is a crys- 
talline solid, melting 54°, insoluble in water, but dissolving in alcohol, 
ether, glycerin, and oils. It is employed as an antineuralgic 

Methyl Benzoyl Salicylate 

Benzosalin is methyl benzoyl salicylate, CeH4- (XCH3) • COO(C6H 5 CO), 
1 : 2 the benzoyl salicylic acid ester of methyl alcohol. 

Benzosalin is prepared by a reaction between the methylester of salicylic 
acid and benzoyl chloride in the presence of sodium hydroxide. 

Benzosalin consists of fine, white crystals with a very faint aromatic 
odor. It melts at about 85° C. It dissolves readily in chloroform, ben- 
zene, and in 35 pans of 90 per cent cold alcohol, also in pure concentrated 
sulphuric acid. 

Benzosalin passes the stomach unchanged and is decomposed into its 
constitutents, benzoic, and salicylic acid in the intestines. 

It is said to be useful in rheumatic affections, such as arthritis, neuralgia, 
sciatica, and migraine, and in arthritis deformans. 

Methyl Salicylate 

Methyl salicylate has been fully discussed in connection with the chem- 
istry of salicylic acid, page 687. 

Methyl Gallate, C 6 H 2 (OH) 3 COOCH3 

Methyl gallate or Gallicin forms grayish-white crystals, melting 192- 
202°, depending on its purity, soluble in water, alcohol, and ether. It is 
used as an antiseptic in eye troubles and as an anticatarrhal. 

Methylenedimethyl Ester, CH 2 (OCH 3 ) 2 

Methylal, formal, or methylenedimethylate is a colorless volatile liquid 
with an odor resembling chloroform. Its specific gravity is .855 at 15°, it 
boils 42° C and it is readily soluble in water, alcohol, and oils. 



ETHEREAL SALTS— PHENOLS 729 

It has anesthetic, hypnotic, and anodyne properties, and is used in 
delirium tremens, insomnia, strychnin poisoning, acute gastric and intes- 
tinal indigestion. When dispensed as a local anesthetic it is usually in 
an ointment or liniment. 

Methylene Dichloride, CH 2 C1 2 

Methylene dichloride is an anesthetic resembling chloroform in its odor 
but boils at 40° and has a specific gravity of 1.377. It burns with a smoky 
flame and dissolves iodin with a brown color. 

Mixtures of chloroform and alcohol are sometimes substituted for 
methylene dichloride, but the fraud is easily detected if the sample is 
diluted with water, and the precipitated heavy liquid tested for its specific 
gravity and boiling-point. 

Ethyl Chloride, C 2 H 5 C1 

Ethyl chloride or hydrochloric ether is also known by several commercial 
names, e.g., kelene. It is used for general anesthesia by inhalation and 
as a local anesthetic. 

It is a colorless, mobile liquid with a penetrating, pungent somewhat 
fragrant odor, boiling 12.5°, specific gravity .851 at 12° C, very volatile 
and inflammable, burning with a smoky green-edged flame and producing 
vapors of hydrogen chloride. It is slightly soluble in water, readily in 
alcohol and ether, and dissolves phosphorus, sulphur, fats, and oils. It 
combines with some of the metallic chlorides such as antimony penta- 
chloride, and ferric chloride, to form crystalline compounds. 

Baskerville 1 states that ethyl chloride intended for anesthetic purposes 
should have the following characteristics : 

1. Its boiling-point should be +12.5°. 

2. On allowing 30 mils to evaporate from a 12J cm. filter paper, no 
foreign or unpleasant odor, especially a garlic odor (indicating phosphorus 
compounds) should be apparent either during or subsequent to evapor- 
ation. 

3. Sixty mils when allowed to evaporate spontaneously should leave 
no weighable residue. 

4. On shaking 10 mils with 10 mils water at 10° C, and then allowing 
the ethyl chloride to evaporate, no odor of acetaldehyde should develop 
on adding 3 drops of potassium bichromate followed by 5 drops of dilute 
sulphuric acid and boiling, nor should a bluish or greenish color develop. 

5. Ten mils dissolved in 10 mils 95 per cent alcohol should give no 
turbidity or precipitate with 3 drops silver nitrate. 

1 J. Ind. and Eng. Chem., 1913, 5, 828. 



730 ORGANIC SUBSTANCES 

The presence of ethyl chloride must be declared on the label of a pack- 
age containing it, as it is a derivative of alcohol. 

Its assay quantitatively is not a simple matter, because it must be 
saponified under pressure and there is so much gas developed that the 
ordinary form of pressure flask will not stand the strain. The result may 
be accomplished, by using a Carius tube, and heating the mixture at the 
temperature of the water-bath. The little ampules should be scratched 
with a file at a point where they may be broken with comparative ease 
when subjected to concussion, and then introduced into the tube, followed 
by alcoholic potash. The tube can then be sealed off, the ampule broken 
by concussion, and after heating, the end of the tube is broken, the liquid 
washed out, the alcohol evaporated, and the chlorine determined by silver 
precipitation. 

Polychlorated ethyl chloride, or Wigger's anesthetic ether, is a mix- 
ture of tri-, tetra- and pentachlorethane. It has an ethereal aromatic 
odor suggestive of camphor, and is used as an anesthetic and irritant. It 
is used chiefly in rheumatic conditions and neuralgia. 

Ethyl Bromide 

Ethyl bromide, C2H5Br, is the hydrobromic acid ester of ethyl alcohol 
containing approximately 1 per cent ethyl alcohol. 

It is a colorless, strongly refractive, easily volatile liquid, having a 
pleasant ethereal odor. It is insoluble in water, but readily soluble in 
alcohol and in ether. It boils at from 38 to 40° C. Its specific gravity 
at 15° is 1.453 to 1.457. 

It is stable when pure but when contaminated with ethyl iodide it 
becomes colored when exposed to light. It burns with difficulty. It is 
very difficultly saponified by potassium hydroxide and it is not attacked 
by sulphuric or nitric acids. Silver nitrate gradually precipitates silver 
bromide. If a mixture of 1 mil ethyl bromide, 5 mils alcohol and 10 drops 
of 15 per cent sodium hydroxide solution is heated to boiling, cooled, 
acidified with dilute sulphuric acid then shaken with chloroform and 
chlorine water added, a brown coloration will be produced in the chloro- 
form layer. If equal volumes of ethyl bromide and sulphuric acid are 
shaken together in a bottle previously rinsed with sulphuric acid and closed 
with a glass stopper, the acid should not be colored yellow within an 
hour. After shaking equal volumes of ethyl bromide and water, no change 
of volume should occur in the two liquids, the water separated from the 
ethyl bromide should not have an acid reaction nor should it become 
turbid immediately on the addition of a drop of silver nitrate solution. 

When a small portion is evaporated from a porcelain plate by cau sing- 
it to flow to and fro over the surface little or no foreign odor is yielded as 



ETHEREAL SALTS— PHENOLS 731 

the last portions pass off, and the plate is covered with a slight deposit 
of moisture. 

One mil of ethyl bromin mixed with 3 drops of anilin and 2 mils of 
alcoholic solution of potassium hydroxide should not give off the odor of 
isonitrile even after warming. (Absence of chloroform.) 

About 1 gram of ethyl bromide accurately weighed added to 30 mils 
of 80 per cent alcohol containing 2 grams silver nitrate will precipitate, 
after several hours, silver bromide, which when washed and dried should 
weigh 1.72 grams for each gram ethyl bromide used. 

Ethyl bromide is a rapid anesthetic, acting much like chloroform. 

Ethyl Iodide, C 2 H 5 I 

Monoiodomethane or hydriodic ether is a clear, colorless neutral 
liquid becoming brown on standing. It boils 70 to 75°, specific gravity 
1.94 at 15°, soluble in alcohol and ether but insoluble in water. It is 
employed as an antispasmodic, anesthetic, stimulant, and alterative, 
and is recommended in chronic rheumatism, scrofula, syphilis, bronchitis, 
and asthma. It is given internally and in the form of an ointment. 

Ethyl Lactate, C 3 H 5 3 C 2 H 5 

Lactic ether is a colorless limpid liquid, sp. gr. 1.031 at 19° C, boiling 
154° C, and soluble in water. It is employed as a sedative and hypnotic. 

Ethylene Dichloride, CH 2 C1CH 2 C1 

Ethylene chloride or Dutch liquid is, strictly speaking, an addition 
product of the unsaturated lrydrocarbon ethylene, and is prepared by 
direct union with chlorine. It is a colorless oily liquid with pleasant odor 
and sweet taste, specific gravity 1.265 at 15° C, boiling 83 to 85°; its 
vapors are irritating to the membranes. It is soluble in alcohol, ether, 
and chloroform, and slightly in water. 

It is used as a substitute for chloroform as an anesthetic, and externally 
is employed in rheumatism. 

Monochlorethylene Chloride, CH 2 C1CHC1 2 

This product, also known as ethylene chloride, monochlorinated Dutch 
liquid, and vinyl trichloride, is a colorless liquid, having a pleasant odor, 
sp. gr. 1.458 at 9° C, boiling 114° and soluble in alcohol and water. It is 
used as an anesthetic in place of chloroform. 

Ethylidene Chloride, CH 3 CHC1 2 

Ethylidene chloride is isomeric with ethylene dichloride. It is also 
termed chlorinated muriatic ether, alphadichlorethane, ethidene bichloride, 



732 ORGANIC SUBSTANCES 

and chloridene. It is a colorless, oily liquid with a chloroform odor, 
sp. gr. 1.178 at 15° C, boiling 58-60° C, and used as an anesthetic and 
analgesic. 

Ethyl Nitrite, C 2 H 5 NO a 

Ethyl nitrite or nitrous ether is known only in the form of the spirit 
of nitrous ether or sweet spirit of niter. The spirit is yellowish in color 
and has a fragrant, pungent odor. The official article contains not less 
than 4 per cent of the ester in alcoholic solution, and has a sp. gr. of .823 
at 25° C, soluble in water and alcohol. It is also sold in a concentrated 
form which can be readily diluted with alcohol to the official strength. 

Ethyl nitrite spirit is employed as a diaphoretic, stimulant, diuretic, 
antipyretic, and antispasmodic. It is used in fevers, colds, dropsy, colic, 
nausea, and genito-urinaiy troubles, and is almost always dispensed alone, 
but for dropsical complaints may be found mixed with squill, Digitalis, 
potassium acetate, or potassium nitrate. For certain states of febrile 
conditions it is mixed with aromatic spirit of ammonia. 

Absolute ethyl nitrite is pale yellow, boiling 17-18° C, with sp. gr. 
.917 to .920 at 0°. 

The assay of spirit of nitrous ether may be accomplished by the same 
procedure as is described under Amyl Nitrite. Factor for Ethyl Nitrite, 
3.07. 

Ethylene Dibromide, CH 2 BrCH 2 Br 

Ethylene dibromide or dibromethane is formed by the direct union 
of bromin and ethylene. It is a colorless crystalline substance below 
9° C. but is usually encountered as a colorless liquid with a chloroform 
odor, sp. gr. 2.189 at 15° C, boiling 129-131° C, miscible with alcohol, 
but insoluble in water. 

It is used in epilepsy and neuralgia, but in small dosage as it is quite 
toxic. 

Ethyl Acetate, CH 3 COOC 2 H 5 

Ethyl acetate or acetic ether is a colorless fragrant inflammable liquid, 
boiling 72-77° C, miscible in all portions with alcohol and ether and with 
17 parts of water. 

The official grade contains about 10 per cent of alcohol and a little 
water. Ethyl acetate is sometimes used internally in nervous affections 
and to revive one after fainting. Externally it is used to a limited extent 
as an anesthetic and antirheumatic. 

The odor of ethyl acetate is characteristic and the formation of this 
substance recognizable by its odor, is used as a test for acetic acid. 



ETHEREAL SALTS— PHENOLS 733 

Ethyl Benzoate, C 6 H 5 COOC 2 H5 

This ester is not used medicinally, but it plays an important part in 
analytical chemistry, as its formation as determined by its odor, is used 
as a test for cocain. It is volatile at all temperatures and boils 212-213° C. 

Ethyl Cinnamate 
Ethyl cinnamate occurs in storax; sp. gr. 1.0531, boiling 257-258°. 

Ethyl Diiodosalicylate, C6H 2 l2(OH)COOC 2 H5 

Diiodosalicylic ether forms white crystals, melting 132°, soluble in 
alcohol and fixed oils and slightly in water. It is used in surgery as a 
substitute for iodoform. 

Ethyl Formate, HCOOC 2 H 5 

Ethyl formate is a mobile, colorless liquid with a peach-kernel odor, 
sp. gr. .917 at 15° C, boiling 54°, miscible in all proportions with alcohol 
and ether and with 9 parts of water. It is used as an hypnotic and analgesic. 

True ethyl formate must not be confused with a substance known as 
" orthoformic " ether, CH(OC2H5)3, which is prepared from chloroform 
and sodium ethylate. This product is a colorless, aromatic liquid, boiling 
145-146° C. 

Ethyl Thiocarbimide, C 2 H 5 NCS 

Ethyl mustard oil is a colorless, pungent liquid, very irritant to the 
tissues and used externally as a local irritant in rheumatism, neuralgia 
and local pains. It boils 133° C. 

Ethyl Valerate, (CH 3 ) 2 CHCH 2 COOC 2 H 5 

Isovaleric ether is a colorless liquid with a pleasant fruity odor, 
sp. gr. .871 at 15° C, boiling 134° C. It is used as a sedative and anti- 
spasmodic in nervous affections, especially asthma. 



Amyl nitrite is the isoamyl ester of nitrous acid. It is a yellow, trans- 
parent, very mobile, volatile, inflammable liquid having a penetrating 
characteristic odor, and a stimulating effect on the senses. Its sp. gr. 
is .870 to .880 at 15° or .865 to 875 at 25°, boiling 97 to 99°, evolving an 
orange-colored vapor, volatile at all temperatures, insoluble in water, 



734 ORGANIC SUBSTANCES 

but dissolving in all the organic solvents. The ester deteriorates rapidly, 
and is usually dispensed in small hermetically sealed glass bulbs. 

The commercial nitrite is probably contaminated with the nitrites 
of other higher alcohols, and furthermore the amyl radicle may be attrib- 
uted to more than one isomeric form. 

Assay, U. S. P. Method. — Transfer about 3 mils of Amyl Nitrite, 
which has been previously shaken with .5 gram of potassium bicarbonate 
and carefully decanted, to a tared 100-mil measuring-flask, containing 
about 20 mils of alcohol, and weigh it accurately. Add sufficient alcohol 
to bring the volume to exactly 100 mils and mix thoroughly. Introduce 
into a nitrometer exactly 10 mils of the alcoholic solution, followed by 
10 mils of potassium iodide T. S., and afterward by 5 mils of diluted sul- 
phuric acid. When the volume of gas has become constant (within thirty 
to sixty minutes), note the amount collected, multiply this volume in 
mils by 4.8 and divide the product by the original weight in grams of the 
Amyl Nitrite. At standard temperature and pressure, the quotient 
represents the percentage of Amyl Nitrite in the liquid. The temperature 
correction is one-third of 1 per cent of the total percentage just found 
for each degree — additive if the temperature is below 25° C, and sub- 
tractive if it is above 25° C. The barometric is four-thirtieths of 1 per 
cent of the total percentage just found for each millimeter — additive 
if it is above 760 mm. and subtractive if it is below 760 mm. 

Assay, Modification of the U. S. P. Method. — Use a saturated salt 
solution in the nitrometer. 

Weigh the amyl nitrite in a closed container and add 13 drops to about 
2 mils of alcohol in the upper tube of the nitrometer and admit to the 
nitrometer tube. Wash out upper tube with 5 mils of alcohol. Then 
add a mixture of 10 mils of potassium iodide solution (1 : 10) and 10 mils 
N/1 sulphuric acid. 

Allow reaction to cease before taking the reading of the NO. Compute 
this reading to normal pressure and temperature. 

Weigh 1 mil NO at N.P.T. = . 001306 gram. 

From this the amount of amyl nitrite can be calculated. 

If one is in any way familiar with drug products the physical proper- 
ties of amyl nitrite are sufficient evidence for its detection. 

It is a powerful cardiac stimulant and antispasmodic and is used by 
inhalation or in capsules for whooping cough, angina pectoris, asthma, 
tetanus, epilipsy, syncope, chloroform asphyxia, etc, 

Amyl Bromide, C 5 H u Br 

Amyl bromide is a clear, Colorless liquid, sp. gr. 1.219 at 15°, boiling 
120 °C, soluble in alcohol and used as a germicide and antiseptic. 



ETHEREAL SALTS— PHENOLS 735 

Amyl Iodide, C 5 HnI 

Amyl iodide is a yellowish liquid, sp. gr. 1.48 to 1.50 at 150° C, boiling 
140 to 148° C, soluble in alcohol, used as a sedative and antiseptic. 

Amyl Salicylate, C 6 H 4 OHCOOC 5 Hii 

Amyl salicylate is a colorless or yellowish liquid, sp. gr. 1.055 to 1.065 
at 15° C, boiling 263-265° C, soluble in alcohol, ether, and chloroform 
and insoluble in water. It is used both internally and externally as an 
antirheumatic. 

Amyl Valerate 

Amyl valerate, CH3 • CHCCHa) ■ CH 2 ■ COCKCH3) • CH 2 • CH 2 ), is the iso- 
valeric acid ester of iso-amyl alcohol. 

It is obtained by separating (by distillation) the ester which is formed 
when valeric acid or soluble valerate is added to a mixture of iso-amyl 
alcohol and sulphuric acid and the distillate obtained, washed, dried, and 
redistilled. 

Amyl valerate is a colorless liquid, having when dilute an odor of apples. 
It is insoluble in water, soluble in alcohol, ether, and chloroform. It 
boils at 188 to 190° C. Its sp. gr. is .858 at 15° C. 

Amyl valerate has been employed in the treatment of gallstone colic. 

Amylene, (CH 3 ) 2 C = CHCH 3 

Amylene, trimethylethylene, or pental is a colorless, mobile inflammable 
liquid, with a disagreeable odor, sp. gr. .666 at 15° C, boiling 35-38° C, 
miscible with alcohol and ether, insoluble in water. It is used as an 
anesthetic in dental surgery. 

Dimethylacetal, CH c CH(OCH 3 ) 2 

Dimethylacetal or ethylidenedimetlvylester is a colorless liquid, specific 
gravity .879 at 0°, boiling 62-63°, miscible with water and the organic 
solvents, and employed as an anesthetic as a substitute for chloroform. 

Carbosant 

Carbosant is santalyl carbonate, (C15H23) -O-COO- (C15H23), the car- 
bonic acid ester of santalol. 

It is an oily yellow fluid, almost tasteless and odorless, insoluble in 
water, and soluble in alcohol and ether. It contains 94 per cent of san- 
talol. 



736 ORGANIC SUBSTANCES 

Carbosant is saponified when heated with an alcoholic solution of 
caustic alkali with the production of potassium carbonate and santalol. 

Carbosant is employed in the treatment of gonorrhea, cystitis, and 
prostatitis. 

Nitroglycerin, C JI d (ON0 2 )3 

Nitroglycerin, glyceryl trinitrate, propenyltrinitrate, or glonoin, is used 
in medicine as a remedy in angina pectoris. Its presence may be expected 
in remedies for heart troubles. It is commonly prepared for administra- 
tion in the form of tablet triturates and pills containing from 10 1 00 to 
■^o grain, and it is also mixed with Strophanthus or Digitalis, or both 
and occasionally with strychnin, spartein, Cactus grandiflorus, belladonna, 
and caffein. Spirit of glonoin is a pharmacopceial product and contains 
1 per cent of nitroglycerin in alcoholic solution. 

Nitroglycerin itself is a colorless or yellowish oil with a sweetish taste, 
sp. gr. 1.6, soluble in ether, sparingly in alcohol, and insoluble in water. 
It may be hydrolyzed by boiling alkalies, yielding glycerin and a 
nitrate, together with a small amount of nitrite owing to secondary reac- 
tions. On reduction with ammonium sulphide it yields glycerin, ammonia, 
and free sulphur. 

Much work has been done on the assay of nitroglycerin tablets, and 
after an extended study Murray of the Bureau of Chemistry has recom- 
mended the following tests: 

Methods for the Determination of Nitroglycerin in Medicinal Tablets. — 
Preparation of the sample. — Crush 25 tablets under 10 mils of ether. A 
25-mil cylindrical graduate makes a convenient container and a stout 
glass rod is used to crush the tablets. Rinse the rod with a little ether, 
allow the insoluble material to settle and decant the solution into a 50- 
mil graduated flask. No special care need be taken to prevent a little 
insoluble material from going into the flask. Wash the residue repeatedly 
with 5-mil portions of ether and decant the washings into the flask until 
it has been filled to the mark. Insert the stopper and mix well. 

Estimation by the Modified Scoville Method. — Place 20 mils of the 
ethereal solution in a carefully dried and tared 50-mil beaker. (A second 
aliquot of 10 mils may be used as a check.) Evaporate the solvent in a 
vacuum desiccator. Apply the vacuum gradually so as to prevent ebulli- 
tion. Leave the beaker in the vacuum thirty minutes after the ether 
has evaporated. Weigh and calculate ether extract per tablet. Treat 
the residue with 2 mils phenoldisulphonic reagent, rotating the beaker 
in such a way that the reagent comes into contact with the entire inner 
surface. After ten minutes add water and wash into a 100-mil flask. 
(If a check analysis as suggested was made, wash this into a 50-mil flask.) 



ETHEREAL SALTS— PHENOLS - 737 

Dilute to the mark and place 10 mils, representing 1 tablet, in a 100-mil 
flask, add about 50 mils water and a few drops more potassium hydroxide 
solution (20 per cent) than is required to neutralize the acid. (Do not 
use sodium hydroxide.) Dilute to the mark and compare the color with 
that produced by a standard nitrate solution similarly treated. Use 
any convenient colorimeter or Nessler tubes. 

Reagents and Standards. — Phenoldisulphonic Acid Reagent. — Dis- 
solve 25 grams of pure white phenol in 150 mils of concentrated sulphuric 
acid, add 75 mils of fuming sulphuric acid (13 per cent SO3), stir well, 
and heat for two hours at about 100°. 

Standard Solution. — Dissolve .7217 gram pure KNO3 in 1 liter of 
water. Evaporate 10 mils of this solution just to dryness on the steam- 
bath. Cool and treat the residue with 2 mils phenoldisulphonic acid 
reagent, observing the precautions noted above and using a glass rod if 
necessary to aid the solution of the residue. After five or ten minutes 
dilute to 250 mils. Each mil of this solution contains .004 mg. nitrogen. 
Add an excess of KOH solution to an aliquot of this solution and dilute 
to 100 mils. It is advisable to prepare a standard of approximately the 
same color as the unknown. Nitroglycerin is 5.4 times nitrate nitrogen. 

Estimation by the Modified Hay Method. — Place 5 mils of the ethereal 
solution in a 50-mil beaker, dilute with 5 or 10 mils alcohol and add about 
5 mils of J per cent alcoholic potassium hydroxide. Cover with a watch- 
glass and allow to stand ten minutes. Place on a steam-bath, allow to 
boil, remove the watch-glass, and when most of the liquid is evaporated 
add about 25 mils water and leave on steam-bath until about half the liquid 
has evaporated or until the odor of alcohol can no longer be detected. 
Cool and dilute to 250 mils. Each mil of this solution represents .01 of 
a tablet. Introduce an aliquot representing .02 to .04 milligram nitro- 
glycerin into a 100-mil graduated flask, dilute with sufficient water to 
make the volume 90 to 95 mils, add 1 drop concentrated hydrochloric 
acid, then 2 mils sulphanilic acid solution and 2 mils naphthylamine 
hydrochloride solution. Complete the volume with water. Prepare at 
the same tune and in the same way standards containing known amounts 
of sodium nitrite. Stopper the flasks and mix well. Compare the colors 
after thirty minutes. Nitroglycerin is calculated by multiplying nitrogen 
found by 8. 

Reagents and Standards. — Sulphanilic Acid Solution. — Dissolve 1 
gram in 100 mils hot water. 

Naphthylamine Hydrochloride Solution. — Under a hood boil .5 gram of 
the salt with 100 mils water for ten minutes, keeping the volume constant. 
Filter and keep in a glass-stoppered bottle. 

Standard Solution of Sodium Nitrite. — To a cold solution of about 2 
grams of sodium or potassium nitrite in 50 mils of water, add a solution 



738 ' ORGANIC SUBSTANCES 

of silver nitrate as long as a precipitate appears. Decant the liquid and 
thoroughly wash the precipitate with cold water. Dissolve in boiling water. 
On cooling the silver nitrite is precipitated. Dry the crystals in the 
dark at the ordinary temperature (preferably in a vacuum). Weigh out 
220 mg. of the dry silver nitrite, dissolve in hot water and decompose 
with a slight excess of sodium chloride. When the solution becomes 
clear, dilute to 1 liter. Dilute 5 mils of this solution to 1 liter. This 
second dilution is the standard to be used. It contains .0001 mg. nitrite 
nitrogen per mil. 

Only nitrite free water should be used in the estimation by the modified 
Hay method. 

Erythrol Tetranitrate 

Tetranitrol, C4He(N03)4, is the tetranitrate of erythrite (butane- 
tetrol), C 4 H 6 (OH) 4 . 

It forms colorless crystalline scales, insoluble in cold water, readily 
soluble in alcohol, melting at 61° C. (141.8° F.) On percussion it ex- 
plodes much like nitroglycerin. 

It is employed in angina pectoris and vascular diseases. 

Nitroglucose 

Nitroglucose is an explosive substance obtained by the action of nitric 
and sulphuric acid on glucose. It is marketed in either an alcoholic or 
aqueous solution of about 5 per cent strength, and is used in epilepsy, 
angina pectoris, and cardiac weakness. 

CHLOROFORM, CHC1 3 

Chloroform is used to a considerable extent as an anesthetic for inha- 
lation, as a counter-irritant, a narcotic, and analgesic. For internal use 
it will be found in remedies for flatulent colic, gastralgia, asthma, cough, 
spasms, hysteria, hiccoughs, scarlet fever, insomnia, and for removing 
gallstones. 

Externally it is administered in the form of liniments for rheumatism, 
neuralgia, colic, etc., and hypodermically for hydrocele. Chloroform is 
also used to a limited extent in some of the artificial flavors used in foods. 

The general run of cough mixtures contain in addition to the chloro- 
form, white pine. bark, wild cherry, sassafras, Sanguinaria, spikenard, 
balsam poplar buds, eriodictyon, and sometimes morphin; or sometimes 
this may be varied by substituting codein and Cannabis indica. Com- 
pound tincture of opium or diarrhea mixture contains opium, camphor, 
Capsicum, and chloroform. Chloranodyne and preparations of the chloro- 
dyne type contain chloroform with morphin, Cannabis, hydrocyanic 



ETHEREAL SALTS— PHENOLS 739 

acid, Capsicum, and peppermint. Chloroform is employed to a con- 
siderable extent in throat lozenges. 

Spirit of chloroform also called chloric ether, consists of about 10 per 
cent of chloroform and 90 per cent of ethyl alcohol by weight. Chloro- 
form water or aqua is official in some of the pharmacopoeias, and is a 
saturated aqueous solution of chloroform. Emulsions of chloroform are 
made with tragacanth, oil of almond, egg yolk, sometimes with the addi- 
tion of camphor. Chloroform hniment is prepared with about 70 per 
cent of soap hniment and 30 per cent of chloroform. 

Chloroform is a colorless, heavy mobile liquid with a characteristic 
odor. Its sp. gr. is 1.49887 at 15° C. and it boils at 60 to 61°, according 
to Baskerville. The anesthetic chloroform on the American market runs 
in specific gravity from 1.4730 to 1.4827 at 25° C. It is not inflam- 
mable, but its heated vapor burns with a greenish flame. It is only 
slightly soluble in water, but is miscible with alcohol and ether, and it is 
an excellent solvent, dissolving many of the alkaloids, resins, fats, gutta 
percha, caoutchouc, balsams, gum chicle, etc. 

Chloroform is readily decomposed by warm alcoholic potash, yielding 
potassium formate and chloride. It gives the carbylamine reaction when 
treated with anilin and alcoholic potash. When brought in contact with 
a solution of alpha- or beta-naphthol in strong potassium hydroxide and 
heated to 50° C. a fine blue color is developed, changing in contact with 
air to blue green, green, green brown and brown. The specifications for 
chloroform intended for anesthetic purposes have been laid down by Dr. 
Baskerville x as follows: 

1. When 100 mils are evaporated over the steam-bath until 10 mils 
remain and the last portions are then allowed to evaporate spontaneously 
from a piece of filter paper, there should result no odor of fusel oil, empyreu- 
matic matter, or other substances than chloroform and alcohol. 

2. One hundred mils should leave no weighable residue on evaporation. 

3. When 20 mils are mixed with 15 mils of concentrated sulphuric 
acid in a glass-stoppered tube of 50 mils capacity previously rinsed with 
concentrated sulphuric acid, no visible coloration should be imparted 
after the addition of .4 mil of pure 40 per cent formaldehyde solution, 
and then shaking thoroughly for five minutes. (Test for organic impur- 
ities.) 

4. When 20 mils of the sample are boiled over 1 gram of clean crystals 
of calcium carbide, and the vapors evolved are passed into ammoniacal 
silver nitrate solution, no acetylene reaction should result. Absence of 
water. 

5. Anesthetic and commercial chloroforms will contain a small quantity 
of alcohol. If it is desired to test for alcohol in a product of higher purity 

i J. Ind. and Eng. Chem., 4, 1912, 576. 



740 ORGANIC SUBSTANCES 

than the above mentioned, 10 mils are shaken in a separatory funnel with 

4 mils of concentrated sulphuric acid, the treatment repeated, and a third 
time with 2 mils. The acid solution is then mixed with 40 mils of water 
and the dilute solution gently distilled until 20 mils have passed over. 
Ten mils of the distillate are treated with 6 drops of 10 per cent potassium 
hydroxide, warmed to 50° C, a saturated solution of iodide in potassium 
iodide added drop by drop, with agitation until the liquid becomes perma- 
nently yellowish brown in color, when it is carefully decolorized with potas- 
sium hydroxide. No iodoform should be deposited. This test is not 
peculiar to alcohol, being produced also by acetaldehyde, propyl alcohol, 
acetone, etc., but pure chloroform should give a negative test. 

6. Pure chloroform complying with the iodoform test is free from 
acetone. Anesthetic chloroform should give a negative test when the 
following procedure is applied: Ten mils of the sample are agitated with 

5 drops of .5 per cent sodium nitroprusside and 2 drops ammonium hydrox- 
ide (sp. gr. .925) and the mixture allowed to stand for several minutes. 
Chloroform containing up to 1 per cent of alcohol may impart a yellowish- 
brown color to the supernatant liquid on agitation, but when acetone is 
present an amethystine color results. The test must be conducted in the 
cold. 

After application to the suspected chloroform direct, the first 10 per 
cent distillate and the 10 per cent residuum obtained by allowing 100 mils 
of the sample to distill slowly should be tested. When the proportion of 
acetone to chloroform is 1 : 500, the amethyst color is marked, but in the 
presence of 1 : 1000 the coloration is not distinct until the whole mix- 
ture has been saturated with ammonium sulphate, shaken, and allowed 
to rest for five minutes. It is advisable to run a blank test on pure anes- 
thetic chloroform for comparison. 

Some acetaldehyde is generally present in fresh and properly stored 
samples of anesthetic chloroform in portions greater than 1 : 3300; usually 
the reaction is not interfered with by this substance, but in every case 
the sample should be examined for the presence of acetaldehyde and if it 
complies with test 7(a) below, a positive reaction upon applying the 
acetone test may be said to be solely indicative of acetone. 

7. The presence of 3 parts of acetaldehyde by volume in 1000 parts 
of chloroform may be detected by the following reaction and smaller 
amounts by resorting to fractionation, and chloroform of all grades should 
comply with the test (a). 

(a) Five mils of the sample are agitated with 5 mils of there agent of 
Francois (20 mils of sulphurous acid, 30 mils 1 : 1000 rosanilin acetate 
solution and 3 mils sulphuric acid) in a glass-stoppered tube; no color- 
ation should result even after fifteen minutes. 

(6) Pure chloroform giving a negative reaction in Test 5 may be 



ETHEREAL SALTS— PHENOLS 741 

regarded as free from acetaldehyde; but it should also give no response 
when 5 mils are agitated with 5 mils Nessler's reagent, U. S. P. and the 
mixture allowed to stand five minutes. 

When 10 mils of anesthetic chloroform are agitated with 10 mils of 
water and 5 drops Nessler's reagent U.S. P., and the mixture then allowed 
to stand for five minutes, there should result no precipitate and the 
reagent should assume no coloration, though it may become opalescent 
or slightly turbid. 

8. When 20 mils of either pure or anesthetic chloroform are thoroughly 
agitated with 10 mils of water and 2 drops of phenolphthalein solution, 
and then titrated with N/100 potassium hydroxide solution, added drop 
by drop, not more than .2 mil of standard alkali should be required to 
produce a faint but decided alkaline reaction permanent for fifteen minutes, 
when the mixture is shaken for thirty seconds after the addition of each drop 
of alkali. 

9. The following tests are conducted in order to detect the decompo- 
sition products of pure chloroform: 

(a) Carbonyl Chloride. — To 15 mils of the sample contained in a 25- 
mil dry glass-stoppered tube, sufficient of a perfectly clear 1 : 19 barium 
hydroxide solution is added to fill the tube. After allowing the mixture 
to stand three hours in a dark place without agitation, the observation 
as to the formation of a film of barium carbonate is made. 

(b) Hydrochloric Acid and Chlorides. — Samples complying with 8 are 
assuredly free from carbonyl chloride, hydrochloric acid and chlorine, 
but pure and anesthetic chloroform should also comply with the following 
test: When 10 mils of the sample are agitated with 5 mils of water for 
five minutes the water extract should not become turbid or give any 
precipitate on adding silver nitrate solution (absence of hydrochloric acid 
or chlorides) and no reduction should occur on warming (absence of 
acetaldehyde, formic acid and formates) . 

(c) Chlorine and Hydrogen Dioxide. — When 10 mils of the sample are 
agitated during fifteen minutes with 10 mils of a 10 per cent cadmium 
potassium iodide solution no iodin should be liberated, as determined 
by the addition of starch solution. Chloroform of all grades should give 
a negative reaction with this test. 

10. The decomposition products of anesthetic chloroform. 

(a) The detection of acetaldehyde has been referred to in 7. 

(b) Anesthetic chloroform failing to comply with 8 should be rejected. 

(c) When 20 mils of the sample are shaken during twenty-five minutes 
with 15 mils of concentrated sulphuric acid in a 50-mil glass-stoppered 
tube previously rinsed with sulphuric acid, and 2 mils are diluted with 
5 mils of water, the liquid should remain colorless and clear and should 
possess no odor foreign to anesthetic chloroform; and the liquid should 



742 ORGANIC SUBSTANCES 

retain its transparency and colorless state when further diluted with 
10 mils of water and the transparency should not be diminished on adding 
5 drops of silver nitrate solution. 

Detection and Estimation of Chloroform. — As chloroform is one of the 
inhibited drugs, its presence in medicinal preparatioms and in food prod- 
ucts must be declared on the label. 

In many cases the characteristic odor will indicate that chloroform 
is present, but of course in others it will be masked by more powerful 
odors, and the peculiar cooling effect which it imparts on inhalation may 
be confused with that given by menthol. 

From liquid mixtures chloroform may be obtained by distillation and 
on diluting the distillate sufficiently if alcohol is present, the chloroform 
will settle out in the bottom of the flask. By distilling with steam, this 
procedure may be made approximately quantitative. The heavy liquid 
which has settled out should be tested further by applying the phenyl 
isocyanide test, and determining its boiling-point. Chloroform boils 
60 to 61°, bromoform 148 to 150°, and carbontetrachloride 76 to 77°. The 
latter does not give the phenylisocyanide test. 

Chloroform can be determined when it occurs in liquid products by 
distilling into a flask, diluting the distillate with water if much alcohol 
is present, and decanting most of the supernatant liquid. The chloroform 
is then treated with 15 to 25 mils of N/1 alcoholic potash and boiled for 
one to two hours under a reflux. The chlorine is then determined by 
precipitating with silver nitrate in presence of nitric acid and the chloro- 
form calculated. 

With some distillates it might be more desirable to add the alcoholic 
potash without previous dilution and decantation. 

Dowzard's x method for the determination of chloroform in lozenges 
is as follows: A weighed lozenge is digested with 70 mils alcoholic potash 
in a 200-mil flask with reflux condenser, warming until dissolved and then 
gently boiling forty-five minutes. Twenty-five mils of water are added 
and a few drops of phenolphthalein, the solution acidified with nitric acid 
and then neutralized with calcium carbonate. After cooling the chlorine 
is titrated with silver nitrate solution, using potassium chromate. A 
blank may be run, using the same quantities of reagents without the 
lozenge, and the difference in amount of chlorine calculated to chloroform. 

Patents have been obtained for a " solid " chloroform w r hich is pre- 
pared by mixing the substance with peptone and allowing the excess to 
evaporate. 

1 Am. J. Pharm., 80, 1909, 511. 



ETHEREAL SALTS— PHENOLS 743 

Bromoform, CHBr 3 

Bromoform, tribromomethane, methenyl tribromide, also called 
"formyl tribromide," is a heavy colorless liquid with an odor resembling 
chloroform. Its sp. gr. is 2.829 to 2.833 at 15° C,, or 2.808 at 25° C, 
boiling 148 to 150 and solidifying 6° C. It is soluble in alcohol and ether, 
somewhat in glycerin, and almost insoluble in water. 

It is not used to any great extent, but is an anesthetic, nervine, and 
sedative, and is employed chiefly in whooping cough. 

It gives the phenylisocyanide test, but its high specific gravity and 
boiling-point distinguish it sharply from chloroform. 

Brometone. Tribrom-Tertiary-Butylalcohol — Acetone-Bromoform 

Brometone, CBr3-C(OH)(CH3) -CH3, is produced by the reaction of 
acetone on bromoform in the presence of caustic alkalies. 

It occurs in fine white, prismatic crystals melting 167°, which possess 
a camphoraceous odor and taste. It is slightly soluble in water, soluble 
in alcohol, ether, benzine and most organic solvents. 

Brometone is claimed to have the sedative action of the bromides 
without the disadvantages of producing bromism. 

Trichlorisopropyl Alcohol. CC1 3 • CH = CH 3 OH 

This substance, known as Isopral, occurs in prismatic crystals, with 
a camphoraceous odor and pungent taste, melting 49° C, soluble in water, 
alcohol, and ether. It is employed as an hypnotic and as a substitute 
for chloral. In its appearance and organoleptic properties it bears a close 
resemblance to chloretone. 

Fluoroform, CHF 3 

Fluoroform is dispensed in an aqueous solution containing about 3 ' 
per cent of the drug in water, known as Fluoroformol or Fluoryl. It is 
odorless and tasteless and is used as an internal antiseptic, alterative, 
and tuberculocide. It is recommended for consumption and pneumonia. 

IODOFORM, CHC1 3 

Iodoform or tri-iodomethane, famous for its powerful and clinging 
odor, is formed when ethyl alcohol (not methyl), acetone, aldehyde, and 
other simple organic substances containing oxygen united with a CH-C 
group are wanned with alkali or an alkaline carbonate. 



744 ORGANIC SUBSTANCES 

It is used to a large extent as an antiseptic, and though attempts are 
often made to disguise its presence, its odor will usually be revealed to 
the operator before he has proceeded far with his investigations. 

It crystallizes in yellow six-sided plates, melting 115 to 119°, and at 
higher temperatures emitting vapors of iodin, sublimable with ease and 
volatile at the ordinary temperature, and with steam. It is very slightly 
soluble in water and petroleum ether, fairly soluble in alcohol, and readily 
in chloroform, ether, fixed and volatile oils. When boiled with alcoholic 
potash it is converted to potassium iodide and formate. 

Iodoform gives the carbjdamine reaction when heated with aniline 
and alcoholic potash. When dissolved in chloroform and a crystal of 
lead nitrate added, a fight rose color appears turning to deep rose and red. 
Bromoform gives on warming a wine red color passing gradually to garnet- 
red and finally to reddish-brown. 

Iodoform unites with many organic bases and sulphocompounds, form- 
ing definite crystalline compounds, many of which possess antiseptic or 
other therapeutic properties, but have not the characteristic penetrating 
odor of iodoform. 

Estimation of Iodoform. — The determination of iodoform is readily 
accomplished by boiling for an hour with alcoholic potash under a reflux, 
evaporating the bulk of the alcohol, diluting with water, acidifying with 
dilute nitric acid, precipitating with silver nitrate, and filtering the silver 
iodide onto a Gooch. 

When working with gauzes or bandages, the sample is introduced 
into a capacious Erlenmeyer, covered with alcoholic potash and boiled 
for an hour under a reflux. The liquid is then decanted, and the textile 
washed with hot alcohol, which is added to the alkaline liquid, and then 
evaporated, the residue taken up with water, acidified with dilute nitric 
acid, filtered if necessary, and the iodin precipitated with silver nitrate. 

Ointments containing iodoform can be similarly treated, but it will 
be necessary, after acidifying, to shake out any oil or separated acid with 
ether. The clear aqueous liquid is then drawn off, the ether expelled by 
gentle heat, and the iodin precipitated with silver nitrate. 

Iodoform will sometimes be found in pills, either alone or with iron 
and quinin; also in globules with cod-liver oil; and in oily inhalants with 
creosote, eucalyptus, etc. 

In order to present iodoform in a condition where it will be less objec- 
tionable, various products have been proposed. Aromatized or deodor- 
ized iodoform is a National Formulary product, prepared by mixing 
iodoform with 4 per cent of coumarin. 

Iodoformin is a product obtained by treating iodoform with hexa- 
methylenetetramine and contains 75 per cent of iodoform. 

Iodoformogen or Diodoform albuminate is a yellow, fine dry powder, 



ETHEREAL SALTS— PHENOLS 745 

about three times as voluminous as the same weight of iodoform and nearly 
odorless. The iodoform is liberated on contact with the wounded surface. 

Ethylene Tetraiodide. Diiodoform, C2I4 

Diiodoform crystallizes in yellow needles, odorless when pure, but 
gradually decomposing on exposure to the light, with the development 
of a characteristic odor. It melts 187° C, is readily soluble in chloro- 
form and benzol, slightly in alcohol and ether, and insoluble in water. 
It is sometimes used instead of iodoform. 

Iothion, CH 2 ICHOHCH 2 I 

Iothion or diiodohydroxypropane is obtained by heating dichlorhydrin 
with potassium iodide in the presence of water. 

It is a yellowish, oily, heavy liquid, of sp. gr. 2.4 to 2.5, containing 
77 per cent of iodin. It is volatile at the body temperature and not 
unpleasantly odorous. It is insoluble in water but soluble in glycerin, 
oils, alcohol, and other organic solvents. It is incompatible even with 
weak alkalies. 

If iothion is heated on the water-bath under a reflux condenser for 
five to six hours, with 33 per cent solution of potassium hydroxide and the 
iodin liberated from the residue by sulphuric acid and sodium nitrate 
and extracted with carbon disulphide, the titration of this iodine carbon 
disulphide solution with sodium thiosulphate in the usual way should 
indicate 77 per cent of iodin. 

Iodanisol, C^OCHsI • (1 • 2) 

Iodanisol, or anisol orthoiodide, is a heavy yellow liquid, sp. gr. 1.8 
at 20°, boiling 240° C, insoluble in water, but soluble in alcohol, ether, 
and chloroform. It is an antiseptic and is sometimes used as a substi- 
tute for iodoform, and is also a local irritant. 

MERCAPTANS AND THEIR DERIVATIVES 

Alcohols form two classes of compounds with hydrogen sulphide, 
the hydrosulphides RSH and the sulphides R2S. The former are called 
mercaptans on account of their combining readily with mercuric oxide, 
forming crystalline compounds. The hydrosulphides or sulphhydrates, 
as they are sometimes called, may be regarded as sulphur- or thioalcohols, 
and the organic sulphides as thio-ethers. 



746 ORGANIC SUBSTANCES 

Ethyl Mercaptan, C 2 H 5 SH 

Ethyl mercaptan may be obtained by treating alcohol with phos- 
phorus pentasulphide, and by distilling a concentrated solution of ethyl 
potassium sulphate with potassium hydrosulphide. 

5C2H5OH+P2S5 = 5C2H5SH+P2O5 
C 2 H 5 KS0 4 +KSH = C2H5SH+K2SO4 

It is a colorless, unpleasant, garlic-smelling liquid, boiling 36°, it burns 
with a blue flame, is sparingly soluble in water but dissolves readily in 
alcohol and ether. It is very volatile and a drop exposed to the air soon 
solidifies on account of the lowering of the temperature due to the evapor- 
ation. 

It is unaffected by caustic alkalies, but sodium or potassium displace 
hydrogen, fomiing the mercaptides C2H5SM, which are crystalline bodies 
soluble in water. 

Mercuric oxide reacts with mercaptan, evolving much heat and form- 
ing a white crystalline inodorous compound, (C^HsS^Hg, which is insoluble 
in water, but may be crystallized from alcohol or strong hydrochloric 
acid. It is unaffected by potash. On oxidation with nitric acid mercaptan 
is converted into an ethyl sulphuric acid, C2H5SO2OH. The sulphonic 
acids formed on oxidation of the mercaptan are relatively strong, and their 
salts differ from the sulphide in not being hydrolyzed when boiled with 
dilute aqueous potash. 

Ethyl mercaptan is not a medicinal agent, but it forms the starting- 
point of a number of important hypnotic drug products, including sul- 
phonal, trional, and tetronal. These bodies are all obtained by subjecting 
ethyl mercaptan and an appropriate ketone to the action of dry hydrogen 
chloride, when condensation takes place and a mercaptol results. On 
oxidizing the latter with permanganate the hypnotic is obtained. Acetone 
gives sulphonal, methyl ethyl ketone gives trional, diethyl ketone gives 
tetronal. 

Sulphonal, (CHs^CiSC^CoHs^, Diethylsulphonedimethylmethane 

Sulphonal forms colorless, odorless, tasteless, prismatic crystals, melt- 
ing 125.5°, slightly soluble in cold water, but dissolving without difficulty 
in boiling water, alcohol, ether, chloroform, and benzol. When heated 
with charcoal, mercaptan is evolved, recognized by its garlicky odor, 
and when heated with sodium acetate, hydrogen sulphide is evolved. 



ETHEREAL SALTS— PHENOLS 747 

Trional, (CHsXCsKoKCSOaCaH^, Diethylsulphonemethylethylmethane 

Trional forms colorless, lustrous, odorless, crystalline scales, melting 
74 to 76° C, fairly soluble in cold water, more readily in boiling water, 
alcohol, and ether. When heated with charcoal or sodium acetate it 
gives the same characteristic tests as sulphonal. 

Tetronal, (C2H 5 )2C(S02C2H 5 )2, Diethylsulpkonediethylmethane 

Tetronal forms colorless lustrous laminae, with camphoraceous odor 
and bitter taste, melting 85°, slightly soluble in water, soluble in alcohol 
and ether. 

These three bodies are used as hypnotics and sedatives and usually 
by themselves in the form of pills, tablets, capsules, or powders. They 
do not give any well-defined color or precipitation tests, but in the general 
scheme of qualitative analysis they will appear on shaking out an acid 
aqueous solution with petroleum ether and ether. In the absence of tests 
indicating other ingredients, portions of the residue should be tested by 
ignition first with charcoal and then with anhydrous sodium acetate, 
and if the mercaptan odor is developed in the former and hydrogen sul- 
phide in the latter, a melting-point determination should be run on the 
recrystallized substance, and the identity of the individual can then be 
established. 

ESTERS OF AROMATIC ALCOHOL 

The esters of the aromatic alcohols have practically no use in medicine. 
Benzyl chloride, iodide, sulphide, and benzyl dichloride are all well 
characterized individuals. 

The cinnamyl and benzyl esters of cinnamic and benzoic acids are of 
importance in this work, as they occur in the aromatic balsams and the 
chemistry of the latter is in large part concerned with the properties of 
the esters. 



Thiophene 
CH=CH 

I! 

CH=CH 



> 



Thiophene, one of the constituents of coal tar, occurs as an impurity 
in benzol, and may be separated therefrom by shaking with concentrated 
sulphuric acid. If the acid contains a trace of isatin (an oxidation product 
of indigo) a blue color develops which is known as the indophenin reaction. 

Thiophene is sometimes used as an antiseptic. 



748 ORGANIC SUBSTANCES 

Thiophene Diiodide, C 4 H 2 I 2 S 

Thiophene diiodide or biniodide in a yellow crystalline substance melt- 
ing about 40° C, soluble in alcohol, ether, and chloroform, and used as 
an antiseptic. 

Thiophene Tetrabromine, C^^S 

This derivative of thiophene is a yellow powder, melting at 112° C, 
and used as an antiseptic. 

THE GLYCEROPHOSPHATES 

Glycerophosphoric acid, as prepared commercially, is a partially 
esterified glycerin compound with phosphoric acid. It is probable that 
only one hydroxyl takes part in the reaction and that two replacable 
hydrogens of the phosphoric acid remain free. 



CH 2 OH 
CHOH 



CH 



OH 
H 



OH 
OP 
OH 



The salts of glycerophosphoric acid were introduced as nerve foods 
and tonics and have become very popular. The most important salts 
found on the market are those of calcium, sodium, and potassium. To a 
lesser extent we meet with those of iron, manganese, quinin, and strychnin. 

The glycerophosphates are usually dispensed in the form of elixirs, 
though sometimes they are given in capsules and of late the manufacture 
of albumin compounds soluble in water is claimed by processess which 
consist in mixing albuminoids (milk casein or vegetable casein) suspended 
in dilute alcohol with the requisite quantity of a glycerophosphate, expelling 
the alcohol by heat and drying; or in mixing the albuminoid with a dilute 
solution of the glycerophosphate, filtering, evaporating to dryness, or 
precipitating with alcohol. Such products are probably more of the nature 
of mixtures than chemical individuals. 

Power, Tutin, and Hann, 1 as the result of an interesting research on 
the glycerophosphoric acids, conclude that the only known products of 
the reaction between glycerin and phosphoric acid are the monoester 
(glycerylphosphoric acid), C3Hs(OH)2 • O • PO(OH)2 ; the diester, 

/\ 
C 3 H 5 (OH)< >PO.OH; 

x o/ 

1 Trans. Chem. Soc, 1905, 249 and 1906, 1749. 



ETHEREAL SALTS— PHENOLS 749 

and the triester (glycerophosphate), C3H5PO4. The first form can have 
the unsymmetrical structure 

CH 2 -OP0 3 H 2 CH2OH 

CH-OH a-acid or the symmetrical CHOPO3H2 /3-acid 

CH2OH CH2OH 

Their investigations indicate that the synthetic product is a mixture of 
the a- and /3-acids, and that this differs from the acid obtained from lecithin 
only by a difference in proportion of the components. 

Glycerophosphoric acid behaves toward methyl orange as a mono- 
basic acid and toward phenolphthalein as a dibasic acid, similarly to 
phosphoric acid. 

Falieres l has worked out a titration method for estimating glycero- 
phosphates which is applicable to the calcium salt: The determination 
is carried out by dissolving .2 gram of the salt in a little water, adding 
20 mils of decinormal oxalic acid, and making up to 100 mils. Fifty 
mils of the filtrate, containing the free glycerophosphoric acid, and an 
excess of oxalic acid, are titrated with decinormal potash and phenol- 
phthalein and twice the number of mils required =A. The calcium 
oxalate remaining on the filter, after well washing with boiling water, is 
dissolved in dilute nitric acid (1 : 10), a few drops of sulphuric acid are 
added, and the solution is titrated with decinormal permanganate = B. 
The quantity of lime is expressed by B X .0028, and for 100 grams of glycero- 
phosphate = BX. 0028X5X100. The formula A+B -20 gives in mils 
of decinormal potash, the weight of the glycerophosphoric acid contained 
in .2 gram of the substance, while (A+B -20) X. 0086X5X100 gives 
the percentage amount of glycerophosphoric acid in the calcium glycero- 
phosphate. 

The neutral organic glycerophosphates and the double salts are all 
amorphous. In the dry state they are stable, but when heated with water 
they decompose. Quinin glycerophosphate on heating in aqueous solu- 
tion, gives on cooling a white precipitate of quinin phosphate. 

For some time the sodium and potassium glycerophosphates were 
known only in a concentrated solution having the consistency of honey, 
but a highly purified dry sodium salt has recently been put upon the 
market. 

The laboratory of the American Medical Association has made a 
thorough study of some of the glycerophosphates, and their results quoted 
below give a very accurate description of the properties of the calcium 
and sodium salts. 

^epert. Pharai., 1898, 10, 8. 



750 ORGANIC SUBSTANCES 



Calcium Glycerophosphate 



Calcium glycerophosphate is monohydrated calcium glycerophosphate, 
Ca(CsH5 (OH)2) PO4, H2O, the normal calcium salt of glycerophosphoric 
acid, H 2 (C3H 5 (OH) 2 )P04, containing not less than 90 per cent of anhy- 
drous normal calcium glycerophosphate. 

Calcium glycerophosphate is a fine white powder, odorless and almost 
tasteless; somewhat hygroscopic. 

It is slightly (about 1 : 400) soluble in water; almost insoluble in 
boiling water; easily soluble in dilute acids; insoluble in alcohol or in 
ether. 

The aqueous solution is alkaline to red litmus paper. A cold, satu- 
rated, aqueous solution yields white, iridescent scales when heated to 
boiling (anhydrous calcium glycerophosphate). 

At about 130° C. calcium glycerophosphate loses its water of hydra- 
tion. When heated above 170° C. the salt is decomposed with evolu- 
tion of inflammable vapors, and at a red heat it is converted into calcium 
pyrophosphate. 

On the addition of ammonium oxalate solution, the aqueous solution 
yields a white precipitate, insoluble in acetic acid or in a solution of citric 
acid, but soluble in hydrochloric acid. With lead acetate solution the 
aqueous solution yields a white precipitate which is soluble in nitric acid. 

If 1 gram of calcium glycerophosphate is dissolved in 10 mils of diluted 
nitric acid and an equal volume of ammonium molybdate test solution 
be added, no precipitate should be formed within one hour. 

If 1 gram of calcium glycerophosphate is dissolved in 100 mils of 1 
per cent hydrochloric acid, the solution should not respond to the U. S. P. 
time-limit test for heavy metals. 

If .1 gram of calcium glycerophosphate is dissolved in 10 mils of 
diluted nitric acid and 1 mil of silver nitrate solution added, not more than 
a distinct opalescence should appear within one minute. 

If .1 gram of calcium glycerophosphate is dissolved in 10 mils of 
diluted hydrochloric acid and 1 mil of barium chloride solution added, 
no distinct turbidity should appear within one minute. 

If 1 gram of calcium glycerophosphate in water is titrated with N/10 
potassium hydroxide, using phenolphthalein as indicator, not more than 
1.5 mils of the alkali should be required. 

If 1 gram of the finely powdered salt is shaken with 25 mils of alcohol, 
the mixture filtered, the filtrate evaporated on the water-bath and the 
residue dried for one hour at a temperature not exceeding 70° C. the residue 
should weigh not more than .01 gram. 

If from .5 to 1 gram of the finely powdered salt is dried to constant 
weight at 130° C, the loss should not exceed 10 per cent. 



ETHEREAL SALTS— PHENOLS 751 

If from .3 to .5 gram of anhydrous calcium* glycerophosphate is 
weighed into a Kjeidahl flask, 10 mils of a mixture of equal parts of fuming 
nitric acid and concentrated sulphuric acid added, the mixture heated 
until oxidation is complete, a little more fuming nitric acid being added 
if necessary, the solution diluted with 50 mils of water and the phosphorus 
determined in the usual way, by precipitation with ammonium molybdate 
and final weighing as magnesium pyrophosphate, the weight should cor- 
respond to from 14.16 to 14.75 per cent of phosphorus. 

If from .3 to .5 gram of anhydrous calcium glycerophosphate is dis- 
solved in 20 mils of a 5 per cent solution of citric acid, 80 mils of water 
added, the calcium precipitated as oxalate in the usual way and weighed as 
calcium oxide, the calcium oxide should correspond to from 18.7 to 19.8 
per cent of calcium. 

Sodium Glycerophosphate 

Sodium glycerophosphate is hydrated sodium glycerophosphate, 
Na 2 (C 3 H5(OH)2)P04 • 5|H 2 0. 

At about 60° C. it begins to lose its water of hydration; when strongly 
heated the salt yields inflammable vapors and at a red heat is converted 
into sodium pyrophosphate. 

The aqueous solution (1 in 20) is alkaline to litmus and to phenol- 
phthalein. 

If an aqueous solution (1 in 20) is acidified with nitric acid, and an 
equal volume of cold ammonium molybdate solution added, it should 
remain clear for one hour. On heating, however, a yellow precipitate 
will be formed. 

The aqueous solution (1 in 100) acidified with hydrochloric acid, 
should not respond to the U. S. P. VIII time limit test for heavy metals. 

The aqueous solution (1 in 100) acidified with hydrochloric acid on 
addition of barium chloride solution should show no distinct turbidity 
within one minute. 

The aqueous solution (1 in 100) acidified with nitric acid should not 
show more than a slight opalescence with silver nitrate solution. 

The aqueous solution (1 in 100) acidified with acetic acid should not 
become turbid within one minute on addition of ammonium oxalate test 
solution. 

If 1 gram of sodium glycerophosphate is thoroughly triturated in a 
mortar with 20 mils of alcohol, the liquid filtered and the alcoholic solu- 
tion evaporated spontaneously the residue, after drying over sulphuric 
acid, should correspond to not more than 1 per cent of the weight of the 
salt taken. 

If 2 to 3 grams of the salt is weighed, dissolved in distilled water and 



752 ORGANIC SUBSTANCES 

the solution titrated with half-normal hydrochloric acid, using methyl 
orange as indicator, the acid consumed should correspond to not less 
than 99 per cent of hydrated sodium glycerophosphate. 

The pure glycerophosphates in aqueous solution are not precipitated 
by heat, but are thrown out by alcohol and ether. They give no immedi- 
ate precipitate with ammonium phosphomolybdate, magnesium mixture, 
nor uranium acetate. The white silver nitrate precipitate is soluble in 
excess of water. The white precipitate given by lead acetate is soluble 
in acetic acid. 

The presence of glycerophosphates in admixtures is usually indicated 
by the non-appearance of a precipitate with ammonium molybdate in 
the cold after considerable time, and a heavy precipitate with the same 
reagent after another portion has been boiled with nitric or hydrochloric 
acid. This test, however, is open to objection if one is working with 
solutions containing a considerable amount of sugar. It is best to make 
a preliminary test with magnesium mixture which will throw out phos- 
phates readily even in presence of sugar or oxalic acid. If no precipi- 
tate is obtained, and on subsequent boiling with nitric acid, neutraliz- 
ing and adding magnesium mixture, a white precipitate comes out which 
is soluble in dilute nitric acid and gives a yellow precipitate with ammonium 
molybdate, the presence of glycerophosphates is established. 

The glycerophosphates resemble the hypophosphites when subjected 
to a high temperature in an ignition tube, for they evolve inflammable 
vapors. They differ from them, however, in their reaction with silver 
nitrate, for while the hypophosphites give a permanent precipitate which 
soon turns black, the glycerophosphate compound is soluble in water. 

If it is desired to determine quantitatively the amount of glycerophos- 
phates in a mixture, the solution should first be neutralized with ammonia 
and an excess of magnesia mixture added to precipitate any free phosphate. 
After filtering and washing, the solution is acidulated with nitric acid and 
boiled under a reflux for an hour or two. The solution is filtered if neces- 
sary, treated with excess of ammonia, and precipitated with magnesia 
mixture. The precipitate is filtered and washed, dissolved in dilute nitric 
acid, precipitated with ammonium molybdate at 60 to 80° C, the pre- 
cipitate washed with hot water, dissolved in ammonia water, the solution 
precipitated with magnesia mixture and allowed to stand overnight. 
The ammonium magnesium phosphate is then filtered, washed with dilute 
ammonia, ignited, and weighed as magnesium pyrophosphate. By cal- 
culating back the amount of glycerophosphoric acid or its salt may be 
obtained. 



ETHEREAL SALTS— PHENOLS 753 



PHENOLS 



Phenols are hydroxy-compounds of the aromatic series in which the 
hydroxy 1 group is attached to the nucleus. They are classed as mono-, 
di-, trihydric, etc., according to the number of hydroxyls present. Car- 
bolic acid and the three isomeric cresols or hydroxytoluenes are mono- 
hydric, resorcinol and its isomers are dihydric, and phoroglucinol is a tri- 
hydric phenol. 

Most phenols are colorless crystalline substances, some possessing a 
characteristic odor, readily soluble in alcohol and ether and to some extent 
in water, the solubility increasing with the number of hydroxy 1 groups. 
The monohydric members volatilize readily, while the trihydric phenols 
usually are decomposed on heating, and distill only moderately with 
steam. 

Phenols yield a violet, blue, or green color with ferric chloride, the 
particular color depending in the case of the di- and trihydric compounds 
on the relative positions of the hydroxy groups. Ortho dihydric phenols 
give a green color, becoming violet and then red on adding sodium bicar- 
bonate, meta compounds a deep violet, and the para a green, immediately 
changing to yellow due to the formation of quinone. 

When the phenols are dissolved in concentrated sulphuric acid and 
treated with a nitroso compound or a nitrite, colored solutions result which 
after diluting and adding excess of alkali become blue or green. This 
is known as Liebermann's reaction. 

The phenolic hydroxyl has certain acid properties, reacting with caus- 
tic alkalies to fonn salts stable in the presence of water, but decomposed 
by carbon dioxide and all other acids with regeneration of the phenols. 
Phenols can thus be removed from ethereal solution by caustic alkalies, 
and recovered by acidulating and shaking out with ether. They are not 
removed by carbonates or bicarbonates, and hence are readily separated 
from acids. 

The metallic phenolates react with alkyl halides and acid chlorides 
to form substances analogous to the ethers and ethereal salts, the former 
being stable to alkalies, the latter undergoing hydrolysis. 

With phosphorus halides, acetic anhydride and acetyl chloride, the 
phenols behave in the same way as the alcohols. On oxidation, however, 
they do not yield aldehydes or ketones. 

Many of the phenols are of medicinal importance, others are of interest 
chiefly as they serve to identify certain drugs or essential oils, and still 
others important in being hydrolytic products of the decomposition of 
glucosides, and hence aid in the identification of the parent substance. 



754 ORGANIC SUBSTANCES 



Phenol or Carbolic Acid, C 6 H 5 OH 



Carbolic acid, or hydroxybenzene, is a powerful antiseptic and will 
often be found as one of the ingredients of a medicinal product. It is 
dispensed with petrolatum, and occurs in ointments combined with zinc 
oxide, menthol, turpentine, tannin, glycerin, and other antiseptic and 
astringent drugs. Some of the most widely advertised ointments and 
medicated soaps contain as the sole ingredient on which any claim of 
virtue can be claimed, a minute quantity of phenol or cresol. 

Solutions of carbolic acid are used for aborting boils, carbuncles, and 
coldsores; for urethral injections and for spraying the throat and nose. 
It is also dispensed with iodin in admixture with glycerin and with sodium 
sulphoricinate. 

The carbolates or phenates of sodium and potassium are antiseptics, 
soluble in water, and used internally in diarrhea, dysentery, and t}"phoid 
fever. Zinc phenate is only slightly soluble in water and is used as a 
dusting powder in surgeiy and skin diseases. Bismuth phenate is used 
as an intestinal antiseptic and for external purpose as an iodoform sub- 
stitute. 

The phenates of quinin and cocain are of commercial importance, the 
latter especially being employed in catarrhal conditions, alone and with 
acetanilid and menthol. A mixture of equal parts of camphor and car- 
bolic acid is used in dyspepsia, flatulency, toothache, etc. 

Pure carbolic acid forms beautiful snow-white crystals having a 
characteristic odor and a caustic action on the skin and flesh. When 
moist it forms a syrupy liquid, and as usually obtained in -analytical work 
it remains in the liquid form. The crystals have a peculiar property of 
gradually turning red, the color appearing in that portion of the mass 
which is furthest from exposure to the air and extending to the surface. 

The crystals melt at 40° C. and the liquid boils at 17&-182° C. It is 
volatile at all temperatures. It is readily soluble in alcohol, ether, chloro- 
form, glycerin, olive oil, and other organic liquids, and dissolves quite 
easily in water. It is practically insoluble in petroleum ether, but the 
absolute acid is miscible, being thrown out if a trace of moisture is present. 
It may be removed from acid solution with ether, and can be shaken out 
of ether or other organic solvents by sodium hydroxide, but not by car- 
bonates. The alkaline phenolate solutions are decomposed by mineral 
acids. On account of the difference in the behavior of phenols and carboxy 
acids toward mild alkalies it is a simple matter to separate them by first 
dissolving in ether and chloroform, shaking out the acids with bicarbonate 
solution, and then removing the phenols by sodium hydroxide. 

An aqueous solution of carbolic acid gives with bromin water a white 
precipitate which at first redissolves and then becomes permanent as more 



ETHEREAL SALTS— PHENOLS 755 

of the reagent is added. It appears to be orange yellow when viewed in 
solution. This precipitate has the composition of tribromphenol bromide. 
On filtering and washing with dilute sulphite and then with water, tri- 
bromphenol is left, which has the composition C 6 H 2 Br 3 OH, and which 
on drying over sulphuric acid melts 95° C. 

When a dilute aqueous solution of carbolic acid is treated with a drop 
of dilute ferric chloride a violet blue color is ob tamed. If an aqueous 
solution is mixed with a little dilute ammonia water and treated with 
sodium hypochlorite solution a blue color develops. 

Albumen and collodion solutions are coagulated by carbolic acid. 
Ortho and para nitrophenols are obtained by treating phenol with dilute 
nitric acid in the cold. The former can be separated from the latter by 
steam distillation. The meta compound is obtainable only indirectly. 
They melt respectively 45°, 96°, 114°. 

Trinitrophenol or picric acid is obtained when phenol is dissolved in 
concentrated sulphuric acid and concentrated nitric acid gradually added. 
It forms brilliant yellow crystals melting 122.5° C. and is of medicinal 
importance. 

When carbolic acid is fused with phthalic anhydride it gives phenol- 
phthalein, w T hich is recognized by the intense beet-red color imparted to 
an alkaline solution. The procedure which is also applicable to all phenols 
is as follows: Equal weights of the sample and reagent, amounting to 
.05 gram, are introduced into a dry test-tube, moistened with a drop of 
concentrated sulphuric acid and heated in an oil-bath at 160° for three 
minutes. The mixture is then cooled, 2 mils of water added and 1 to 2 
mils of dilute sodium hydroxide. 

Resorcin gives fluorescein, guaiacol gives a violet blue to violet color, 
orcin orange red. 

When carbolic acid is dissolved in chloroform, a small piece of potas- 
sium hydroxide added and boiled, the liquid gradually assumes a pink 
color. Other phenols give more or less characteristic colors. 

In the general scheme of qualitative analysis carbolic acid will appear 
as an oily residue on evaporating the ether shake-out from acid solution. 
If it is present in marked quantity its odor will distinguish it, and its 
presence can then be further substantiated by dissolving a small quantity 
in water and testing the solution with ferric chloride. The tribrom deriv- 
ative should then be prepared and its melting-point determined and the 
phthalein fusion performed. 

If the presence of carboxy acids is suspected the residue should be dis- 
solved in ether and shaken with sodium bicarbonate solution in order to 
remove them. The phenol can then be shaken out with sodium hydroxide 
and recovered by adding excess of mineral acid and shaking out with ether. 

When carbolic acid occurs in ointments or in oily mixtures, it can be 



756 ORGANIC SUBSTANCES 

determined by dissolving a weighed portion in ether and extracting the 
solution three times with dilute sodium hydroxide. The alkaline solution 
is acidulated with hydrochloric acid and if a precipitate occurs due to fatty 
acids, the liquid is cooled, filtered, the filter washed with water, the acid 
liquid treated with an excess of bromin water, stoppered, and allowed to 
stand until the precipitate has agglomerated, when it is filtered onto a 
tared Gooch, washed with sulphite solution, and then several times with 
cold water. It is then dried over sulphuric acid and weighed. 

Soaps should be dissolved in warm water and the solution precipitated 
with hydrochloric acid. When the fatty acids have separated, the mix- 
ture is poured onto a wet filter paper and the precipitate washed several 
times with water. The phenol which now is present in the filtrate and 
washings is ready for the bromin precipitation. 

The pharmacopceial method for the evaluation of this substance is 
as follows: 

Dissolve about 1.5 grams of the Phenol to be assayed, accurately 
weighed, in sufficient distilled water to make 1000 mils. Transfer an 
aliquot portion of this solution, containing not less than .038 gram not 
more than .041 gram of Phenol, to a 500-mil glass-stoppered flask having 
a long, narrow neck, add 30 mils of N/10 bromine V. S., then 5 mils of 
hydrochloric acid, and immediately insert the stopper. Shake the flask 
repeatedly during half an hour, allow it to stand for fifteen minutes, 
remove the stopper just sufficiently to introduce quickly 5 mils of an 
aqueous solution of potassium iodide (1 in 5), being careful that no bromin 
vapor escapes, and at once stopper the flask. Shake the latter thoroughly, 
remove the stopper and rinse it and the neck of the flask with a little dis- 
tilled water, so that the washings may flow into the flask, then add 1 mil 
of chloroform, shake the mixture well and titrate with N/10 sodium thio- 
sulphate V. S., using starch T. S. as indicator. It shows not less than 
97 per cent of C 6 H 5 OH. 

Each mil of N/10 bromin V. S. corresponds to .001568 gram of 
C6H5OH. Each gram of Phenol corresponds to not less than 618.6 mils 
of N/10 bromin V. S. 

Trinitrophenol or Picric Acid, C 6 H 2 (N0 2 )30H 

This substance is almost universally known as picric acid, and is remark- 
able for its brilliant yellow color, which persists even in very dilute solu- 
tions. It melts 122.5°, soluble in alcohol, ether, chloroform, and to a 
moderate extent in water. It has strong acid properties, decomposing 
carbonates and forming explosive salts. The potassium salt is sparingly 
soluble in water, but the sodium compound dissolves with ease. 

Picric acid gives precipitates with many of the alkaloids and an especi- 



ETHEREAL SALTS— PHENOLS 757 

ally insoluble compound with antipyrin. It coagulates albumen and 
gelatin, and forms crystalline compounds with benzol, naphthalene, 
anthracene and many other hydrocarbons, so that it is sometimes used in 
detecting and purifying small quantities of these substances. 

It is removed from its solution in mineral acids by immiscible solvents, 
and may be identified by the above-mentioned properties and by its dyeing 
of silk and wool, but not cotton. It can be titrated with alkali, using 
phenolphthalein as an indicator. 

Picric acid is an antiseptic. The acid and its salts are used in malaria 
and trichimasis ; externally for burns, hemorrhage, erysipelas, eczema, etc., 
and as an injection for gonorrhea. Picric acid gauze is an important 
agent in surgical practice. 

The silver compound is called Picratol, and is used as an antiseptic 
in gonorrhea and in catarrhal affections of the throat and nose. 

Tribromphenol, C 6 H 2 Br s OH 

Tribromphenol or Bromal is a white to reddish crystalline powder 
with a bromin-like odor. It melts 95°, is insoluble in water, but dis- 
solves in the ordinary organic solvents. 

It is employed as an external and internal antiseptic. It is given in 
cases of typhoid fever, cholera infantum, etc., and externally is applied 
to wounds and running sores, and in the form of glycerin solution in diph- 
theria. It is often dispensed in an oily medicine or in the form of an 
ointment. 

A product of somewhat uncertain composition, but claiming to be a 
bismuth tribromphenate is known as Xeroform. It contains 57 to 61 
per cent Bi2C>3, and is a yellow, neutral, insoluble powder possessing the 
combined virtues of bismuth and tribromphenol. 

According to the patent it is obtained by dissolving tribromphenol 
in sodium hydroxide and adding bismuth nitrate to the sodium tribrom- 
phenolate solution. The precipitated tribromphenol bismuth is collected 
and washed with alcohol. 

It is insoluble in water, alcohol, chloroform, liquid petrolatum, and 
vegetable oils, but soluble in 2 per cent hydrochloric acid in the propor- 
tion of 30 : 100. By alkalies it is decomposed with the formation of 
bromides; it is not decomposed by heat at temperatures below 120° C. 

It should yield 59.5 per cent of bismuth oxide. If 1 gram is boiled 
with sodium hydroxide T. S. filtered, the filtrate rendered acid with sul- 
phuric acid and the white, curdy precipitate washed and dried, it should 
melt at 95° C. 

It is useful as an odorless and efficient substitute for iodoform in 
weeping eczemas; internally, in gastrointestinal catarrh, proctitis, dysen- 
tery, bacillary and choleraic diarrhea, cholera infantum, etc. 



758 ORGANIC SUBSTANCES 



Paraiodophenol, C 6 H 4 OHI 



Phenol iodide is a colorless or reddish crystalline substance melting 
about 92°, used as an antiseptic by itself or in glycerin admixture and is 
applied in diphtheria, cancer, leucorrhea, ringworm, and other diseases 
where a strong antiseptic is indicated. 

Ethyl Carbolate, C c H 5 OC2H 5 

The ethyl ester of phenol known as Phenetol is an oily liquid, boiling 
172°, soluble in alcohol and ether. 

The Cresols, C 6 H 4 OH • CH 3 

The three isomeric cresols occur in coal tar and a purified mixture of 
the three compose the pharmacopceial product known as cresol or cresylic 
acid. It is used as a disinfectant and antiseptic either by itself or in admix- 
ture with soap. Large quantities of crude cresol are used in the manu- 
facture of sheep and cattle dips. Household antiseptics of the creolin 
and lysol type contain essential quantities of neutralized cresols. 

The cresols resemble carbolic acid in most of their properties; they 
form sodium and potassium cresylates, which are decomposed by carbon 
dioxide and by stronger mineral acids, so that on acidifying an alkaline 
solution they may be shaken out with ether. They yield alkyi derivatives 
by the displacement of the hydrogen in the hydroxyl group, and on dis- 
tillation with zinc dust they are all converted into toluene. They give 
blue colors with ferric chloride. 

Ortho cresol melts 31°, boils 188°; meta melts 5°, boils 201°; para 
melts 36°, boils 198°. 

The presence of the hydroxyl group in the cresols protects the methyl 
group from the easy oxidation which characterizes the methyl group of 
toluene. However, if the hydrogen of the hydroxyl is replaced by a radicle, 
the protective influence is removed and substances like methyl cresol, 
C6H4CH3 • OCH3, are readily oxidized to benzoic acid derivatives. 

The cresols are soluble in water to some extent, and mix in all propor- 
tions with alcohol, ether, and petroleum ether, differing in this last respect 
from carbolic acid. 

Estimation of Cresols or Cresylic Acid in Cattle Dips. — Chapin. — 
Fifty grams of coal-tar cresote or 15 to 20 grams of cresylic acid dip are 
weighed into a 500-mil round-bottomed flask, 20 mils of 1 : 3 H2SO4 are 
added, and the phenols are distilled off with steam. The flask will require 
no heating if a rapid current of steam is passed into it, but may with advan- 
tage be packed in cotton or felt. Obviously the apparatus must be so set 
up and the distillation so conducted that particles of resin may not be 



' 



ETHEREAL SALTS— PHENOLS 759 

mechanically carried over by the current of steam. Toward the end of 
the distillation any naphthalene in the condenser is melted out by shutting 
off the water for a few minutes, or if separated earlier in sufficient quantity 
to threaten stoppage of the condenser tube, distillation is interrupted 
while hot water is run through the condenser. The distillate is received 
in a liter flask approximately marked for each 100-mils capacity and joined 
to the condenser by a cork, which is pierced by a small glass tube connected 
to a small U-tube containing a little dilute caustic soda. The latter acts 
as a trap to prevent any loss of the distilled phenols. Distillation is 
continued untill 1 or 2 mils collected in a test tube gives no reaction 
with any appropriate reagent for phenols, such as ferric chloride. A 
volume of 800 mils is ample in nearly all cases. 

A supply of benzol should be prepared by shaking a good grade of 
benzol with dilute sulphuric acid, then with dilute caustic soda two or 
three times, and then passing through a dry filter. A small wash bottle 
containing some of this benzol will be found very useful for rinsing the 
necks of separatory funnels, etc. Of this purified benzol 150 mils are 
measured out conveniently at hand, the contents of the U-tube and 5 
mils of 1 : 1 H2SO4 are added to the distillate, and the latter is shaken 
up and poured into a separatory funnel of 1500 mils capacity, the flask 
being rinsed out with successive portions of the 150 mils benzol. When 
all is in the funnel 25 grams of clean sodium chloride is added for each 
100 mils of distillate, and the funnel well shaken for five minutes and left 
at rest one-half hour. The aqueous layer is then run off slowly and com- 
pletely, the funnel being allowed to stand until there is no further separa- 
tion. The benzol solution of phenols and hydrocarbons is transferred 
to a 500-mil Erlenmeyer flask, while the aqueous portion is poured back 
into the separating funnel and extracted twice more in the same way, 100 
mils of benzol being used each time. The funnel should always be gently 
handled after the aqueous portion has been drawn off, to prevent any 
impurities from the sodium chloride which have deposited upon its sides 
from becoming mixed with the benzol solution. The three benzol extracts 
are united in the Erlenmeyer flask, 15 mils of pure caustic soda solution, 
1 : 2, is added, and the contents of the flask are subjected to a rotatory 
motion for some time in order that the phenols may be taken up by the 
caustic soda as completely as possible. 

After the addition of a few grains of sand the flask is immersed in a 
water-bath, connected to a condenser, and all but 40 to 50 mils of the 
benzol distilled off. With the aid of a wash-bottle containing water and 
provided with a fine jet, only a small portion of water being used at a 
time, the contents of the flask are next carefully washed into a 150-mil 
separatory funnel. With proper manipulation the flask should be com* 
pletely washed when the volume of aqueous portion in the separatory 



760 ORGANIC SUBSTANCES 

tunnel amounts to not more than 50 mils. Ten mils of strong sulphuric 
acid (100 mils pure concentrated H2SO4 to 120 mils water) is next slowly 
introduced with gentle rotation of the funnel, the addition of acid being 
interrupted and the funnel cooled whenever it becomes unpleasantly 
warm to the hand. Two or three drops of methyl orange are now added; 
and if on mixing the contents of the funnel the lower layer does not acquire 
a pink color. tLe addition of acid is continued until acidity is assured. 
Sufficient benzol is then added to make the two layers in the funnel approxi- 
mately equal in volume, the funnel is thoroughly shaken, and with loosened 
stopper, left at rest for two hours. After that time the aqueous layer is 
slowly and completely run out, the analyst making sure that on longer 
standing no more will drain down from the sides of the funnel. The benzol 
solution of phenols is then readjr to be transferred to the measuring tube. 

The measuring tube consists of a glass-stoppered pear-shaped bulb 
of about 100 mils capacity, joined at its tapering end to a tube about 1 
foot long and of a capacity of 25 to 30 mils. This tube is accurately 
graduated to contain 25 mils at 20° C. in divisions of one-tenth mil. 

The apparatus is cleaned thoroughly with soap powder and hot water, 
and dried, best spontaneously, though alcohol and ether may be used if 
pure. Perfect cleanliness is essential to insure a properly shaped meniscus. 
Between 15 and 16 mils of caustic soda solution, 1 : 3, is brought into 
the tube with a pipette. The caustic soda should not be allowed to come 
in contact with the interior of the bulb or the upper part of the tube. 
After a few moments about 1 mil of benzol is added, and after waiting a 
little the height to the top of the now almost flat meniscus is noted. The 
benzol solution of phenols is next transferred from the separators funnel 
to the tube, care being used to avoid mixing with the soda; the separatory 
funnel is washed out with a little benzol, which is also transferred to the 
tube, and the height of the meniscus is again noted. The latter may 
often be obtained more accurately at this point. The tube is then stop- 
pered, vigorously shaken for three minutes, and set aside for at least three 
hours. An occasional rapid rotation of the tube between the palms of 
the hands will insure a complete separation of the layers. Each mil 
increase in volume of the caustic soda solution may be taken to represent 
one gram of phenols. All readings of the tube should be taken at the top 
of the meniscus and at a temperature as near 20° C. as practicable. 

Europhen 
Di-Isobutyl-Cresol Iodide, 

C 6 H3(C 4 H 9 )(CH3)(OI)-C 6 H2(CH3)( : 0)(.C 4 H 9 ), 

is a condensation product of 2 molecules of isobutylorthocresol, with 1 
atom of iodin, analogous to thymol iodide. 



ETHEREAL SALTS— PHENOLS 761 

It forms a yellow, voluminous powder, fusing at 110° C, containing 
28 per cent of iodin, and having a faint saffron-like odor. It is insoluble 
in water or glycerin, but readily soluble in alcohol, ether, chloroform, 
and the fixed oils. It is permanent in the dry state, but splits off iodin 
readily when moistened and rapidly when heated with water at 70° C, 
particularly in the presence of alkalies. 

When triturated with glycerin and water, it yields a filtrate which is 
turned bluish by the addition of freshly prepared starch paste. Its alco- 
holic solution produces a yellow precipitate with mercuric chloride. 

Triiodometacresol or Losophan, C 6 HI 3 OHCH 3 

Losophan is a colorless, crystalline body with a strong characteristic 
odor. It is insoluble in water and only slightly in alcohol, but dissolves 
in ether and chloroform and is used in alcoholic solution or in ointments 
for eczema, acute inflammation and parasitic skin diseases. 

Cinnamylmetacresol or Hetacresol 

This is a white crystalline powder, insoluble in water, but dissolving 
in ether, in which solution it is used as an antiseptic wash for sores, fistulas, 
and tubercular lesions. 

The Cresalols 

The cresylic esters of salicylic acid are called cresalols, 

CeHiOHCOOCeEUCHa. 

They are all white crystalline powders soluble in alcohol and ether and 
insoluble in water, the ortho, melting 35°, is not of importance therapeu- 
tically; the meta, melting 74°, and the para, melting 39°, are used for the 
same purposes as salol. 

Cre satin 

Meta-cresyl acetate is the acetic acid ester, CH 3 C6H4-0(CH 3 CO), 
of meta-cresol, CHsCeHi-OH. 

Cresatin occurs as a colorless, oily liquid, possessing a characteristic 
odor. It is practically insoluble in water, but soluble in the ordinary 
organic solvents, miscible with liquid petrolatum, fixed and volatile oils 
and is volatile with steam. 

It is said to be useful in the treatment of affections of the nose, throat, 
and ear. 



762 ORGANIC SUBSTANCES 



Thymol, CH 4 (CH 3 )C 3 H 7 



Thymol, which is isomeric with carvacrol, is a monohydroxy-derivative 
of cymene. Constitutionally it is 

CH3 

/ 

\ 



OH 
CH(CH 3 ) 2 

Thymol has attained considerable reputation as an antiseptic and 
anthelmintic. It is usually a component of mouth washes and gargles, 
and will often be found in tooth pastes and powders. It is used internally 
for rheumatism, gout, typhus fever, whooping cough, influenza, and gastric 
fermentation and as an expellant of the hook-worm. Its presence may be 
suspected in remedies intended for any of the above diseases. 

The various combinations of mouth washes and gargles are too numer- 
ous to describe, but any of the listerine type or the glycothymoline type 
will probably contain thymol. One type of " shot gun " formula recom- 
mended as an astringent and antiseptic for leucorrhea contains thymol, 
eucalyptol, tannic, salicylic and boric acids, alum, and the extracts of 
Hyoscyamus, opium, helonias, and witch hazel, sold in tablet form. 
Nasal tablets contain thymol, menthol, eucalyptol, methyl salicylate, 
and the bicarbonate, borate, chloride, benzoate, and salicylate of sodium. 

Thymol occurs in the volatile oil of Thymus vulgaris the common or 
garden thyme, in the volatile oils of Monarda punctata, Morula japonica, 
Cunila mariana, and Carum ajowan. 

Thymol forms colorless transparent crystals, with a characteristic 
thyme-like, pleasant odor, melting 50-51° and boiling 220-322°. It dis- 
solves but slightly in water, but is readily soluble in alcohol, ether, chloro- 
form, petroleum ether, glacial acetic acid and the fixed oils. It forms 
soluble salts with alkalies. When triturated with camphor, menthol or 
chloral hydrate, a liquid is produced. It gradually volatilizes at the tem- 
perature of the water-bath. 

An aqueous solution of thymol does not give a blue color with ferric 
chloride, but a concentrated solution in alcohol gives a transient blue 
color with a trace of the very dilute reagent. If a small crystal is dis- 
solved in 1 mil of glacial acetic acid and treated with 6 drops of concen- 
trated sulphuric acid and 1 of nitric acid, a deep bluish-green color will 
appear. 

A solution of thymol in sodium hydroxide when agitated with chloro- 
form develops a violet color. 



ETHEREAL SALTS— PHENOLS 763 

A veiy characteristic test for thymol consists in dissolving a suspected 
residue in a small quantity of sodium hydroxide solution and adding 
slight excess of a solution of iodin in potassium iodide, when a brilliant 
red precipitate of di-thymol diiodide will gradually settle out. This 
substance is insoluble in water but dissolves in ether. It has the compo- 
sition C20H24O2I2. 

If 1 gram of thymol is dissolved in 1 mil of concentrated sulphuric 
acid, added to a mixture of 1 mil each of nitric acid and sulphuric acid 
and subjected to the temperature of a boiling water-bath for three to 
four minutes, trinitro thymol is formed, which may be obtained in a pure 
condition by pouring the mixture into 20 mils of cold water, cooling, 
shaking, filtering, washing, and then recrystallizing from a mixture of 
10 mils water, 4 mils alcohol and .5 mil concentrated hydrochloric acid. 
It melts 109 to 110°. 

When fused with phthalic anhydride the product has a violet-red to 
red color, which dissolves in sodium hydroxide with an intense blue. 

When it is desired to determine thymol in admixture with other anti- 
septic agents such as are usually found in dentifrices, douches, etc., a 
measured quantity of the sample is introduced into a distilling flask 
arranged for steam distillation, with an outlet tube in the form of a spray 
trap such as is used in running Kjeldahl distillations. The material is 
diluted with water, acidulated with phosphoric acid, and distilled with 
the aid of a current of steam. The distillate is recovered in a flask closed 
as tightly as possible and surrounded with cold water. The amount of 
liquid to be collected depends on the nature of the sample, but it is well 
to continue the operation for half or three-quarters of an hour. The dis- 
tillate is tested for acidity and if the reaction is acid a slight excess of 
sodium bicarbonate* is added. It is then transferred to a separator and 
shaken out two or three times with ether, the ether extracts united, shaken 
with dilute caustic alkali, the alkaline solution transferred to a distilling 
apparatus of the type above described, acidulated with phosphoric acid 
and the thymol distilled off, collecting the distillate in a glass-stoppered 
flask. The estimation of the thymol in the distillate then follows the 
procedure of Seidell. 1 One mil of carbon tetrachloride is added and then 
bromin vapor poured in, a little at a time with alternate shaking and 
addition of bromin until the mixture retains a distinct brown color. 
After allowing to stand in a dark place for one-half hour, 5 mils carbon 
sulphide followed by 5 mils of 20 per cent potassium iodide solution 
are added, the bottle well shaken, N/10 thiosulphate run in until the 
pink color in the carbon bisulphide layer is just discharged, an additional 
amount of potassium iodide added, when if no further liberation of iodin 
occurs, the reading of the burette is taken. Five mils of 20 per cent potas- 
1 Amer. Chem. Journal, 47, 508. 



764 ORGANIC SUBSTANCES 

sium iodate solution are added, the flask well shaken, and titration with 
thiosulphate continued until the iodin color is discharged a second time. 
The completion of the reaction may be tested by a further addition of 
iodide and iodate solutions. The difference between the first reading 
and the second corresponds to the hydrobromic acid formed by the action 
of the bromin on the thymol. The calculation is made on the basis of 
2 molecules of hydrobromic acid to one of thymol. One mil N/10 thio- 
sulphate is therefore equivalent to .0075056 gram of thymol. 

Assay of Thymol. — The weighed sample of .1 to .5 gram of thymol is 
placed in a 300-mil stoppered bottle with 1 to 2 mils of carbon tetrachloride 
and 100 mils of water. Bromin vapor is then poured into the mixture 
till there is considerable excess after shaking. After half an hour, 5 mils 
of carbon bisulphide and 5 mils of 20 per cent potassium iodide solution 
are added, and the free iodin is titrated by means of N/10 thiosulphide 
solution. After adding a little more iodide, no further liberation of 
iodin should take place. Five mils of 2 per cent potassium iodate solu- 
tion are then added, and the free iodin again titrated. The result is 
calculated as above described. 

Dithymol diiodide, (QI^CHsOICsHt^ 

This substance which we will call simply thymol iodide, is extensively 
used as a substitute for iodoform in antiseptic dusting powders, medicated 
gauzes, and bandages. It is sold under a number of different names 
including aristol, thymoto, iodistol, iodohydromol, iodothymol, iodosol, 
iosol, iothymol, thymiode, thymodin, etc. 

Thymol iodide is a bright-red or pinkish red powder with a slight odor 
and a chalky feel. It is insoluble in water and only ^slightly in alcohol, 
but dissolves readily in ether, chloroform, and oils. On exposure to 
light it is gradually decomposed. 

U. S. P. Method of Assay. — Mix thoroughly about .25 gram of Thymol 
Iodide, previously dried to constant weight in a desiccator over sulphuric 
acid and accurately weighed, with about 3 grams of anhydrous sodium 
carbonate. Cover the mixture with about 1 gram more of anhydrous 
sodium carbonate and heat it moderately, in a crucible, gradually increas- 
ing the heat, but not exceeding a dull redness, until the mass is completely 
carbonized. When sufficiently cooled, extract the residue with boiling 
distilled water and wash it on a filter with boiling distilled water until 
the washing ceases to produce an opalescence with silver nitrate T. S. 
Heat the combined washings, which measure about 150 mils on a water- 
bath and add an aqueous solution of potassium pemanganate (1 in 20) 
in small portions, until the hot liquid remains permanently pink. Then 
add just enough alcohol to remove the pink tint, cool the liquid to room 






ETHEREAL SALTS— PHENOLS 765 

temperature, and dilute it to 200 mils. Mix it well and then filter through 
a dry filter, rejecting the first 50 mils of filtrate. To 100 mils of the sub- 
sequent clear filtrate add about 1 gram of potassium iodide (free from 
iodate) and an excess of diluted sulphuric acid, and titrate the liberated 
iodin with N/10 sodium thiosulphate V. S., adding starch T. S. near 
the end of the titration. It shows in the dried Thymol Iodide, not less 
than 43 per cent of I. 

Each mil of the N/10 sodium thiosulphate V. S. used corresponds 
to .002115 gram of I. Each gram of Thymol Iodide corresponds to not 
less than 203.3 mils of N/10 sodium thiosulphate V. S. 

Thymol Salicylate, C 10 Hi3OC 7 H 5 O3 

Thymol salicylate or salithymol is the reaction product of sodium 
salicylate with sodium thymolate and phosphorus tri-chloride. It is a 
white crystalline powder, soluble in alcohol and ether and slightly in water, 
used as an antiseptic. 

Thymol Carbonate 

Thymol carbonate, thymotol, or tyratol is a derivative of thymol 
obtained by passing phosgene gas into a solution of sodium thymolate. 
It forms colorless crystals with a faint odor of thymol, soluble in alcohol, 
ether, and chloroform and insoluble in water. It is used as a vermifuge. 

Thymoform 

Thymoform is a condensation product of thymol and formaldehyde, 
soluble in alcohol, ether, chloroform, and oils, insoluble in water, and used 
as a substitute for iodoform. 

Carvacrol 

Carvacrol has the constitution 

CH3 
OH 



CH(CH 3 ) 2 

showing its close relationship to thymol. It is a liquid of specific gravity 
.981 at 15 °C, melting +.5° C, boiling 236-137° C, its alcoholic solution 
giving a green color with ferric chloride. In odor and general character- 
istics it is very similar to thymol. In concentrated solution with alcohol 



706 ORGANIC SUBSTANCES 

it gives a transient dirty-green color with a small quantity of dilute ferric 
chloride. 

This phenol often accompanies thymol in oil of thyme from certain 
sources, in fact sometimes replaces its isomer entirely. Its chief sources, 
however, are the oils of several species of Origanum. The oil of 0. vul- 
gare, Wild Marjoram, is used as an antiseptic and emmenagogue, and in 
the trade the oil commonly called " oil origanum " is really thyme oil. 

Cretan origanum oil, of which there are two varieties, the Triest and 
Smyrna oil, has no special interest to the drug chemist. 

Dihydric Phenols 

The dihydric phenols and their derivatives furnish a number of interest- 
ing and important medicinal bodies. . The relationship of the three iso- 
meric dihydric phenols is apparent from the following f ormulae : 

OH OH 

I 




I 
l-OH 



OH 

Catechol or Ortho-dihydroxy- Resorcinol or Meta-dihydroxy- Hydroquinone or Para-dihydroxy- 
benzene benzene benzene 



Catechol, C 6 H 4 (OH) 2 

Catechol or pyrocatechin is widely distributed in nature, being associ- 
ated with the tannins occurring in a great variety of plants, these par- 
ticular tannins giving a greenish-black or greenish-brown color with 
ferric chloride. It is present in catechu or cutch, an extract prepared 
from the wood of Acacia catechu, and is used as an astrigent. 

Catechol is a colorless crystalline substance, melting 104° C, readily 
soluble in water, alcohol, and ether. Its aqueous solution gives a green 
color with ferric chloride, changing to violet and red on the addition of 
sodium bicarbonate and being restored to green on the cautious addition 
of sodium hydroxide. It reduces alkaline copper sulphate and silver 
nitrate in the cold, and gives a precipitate with lead acetate. In presence 
of alkalies it absorbs oxygen from the air, becoming brown and black; 
lime water causes a reddish or brown color. Pine wood moistened with 
hydrochloric acid is colored blue by a solution of catechol. 

Catechol is an antiseptic and antipyretic and is used externally in 
solutions and ointments for burns, wounds, etc. 



ETHEREAL SALTS— PHENOLS 767 

Aqueous solutions of catechol are neutral, but on adding borax the 
liquid acquires acid properties and decomposes carbonates. Pyrogallol 
and gallates of the alkalies act in the same way, but resorcinol, hydro- 
quinone, and orcinol do not. 

When the phthalein fusion test is applied, the melt gives a blue color 
with alkali. 

Catechol is used to a limited extent as a remedial agent, but several 
of its derivatives are of marked importance. The monomethyl ester is 
well known as guaiacol, the dimethyl ester as veratrole, the monoethyl 
ester as guaethol, and the methyl benzyl ester as brenzcain. The sodium 
salt of its acetate, CeELiOH • OCH 2 COOXa, is called guaiacetin, and is 
used in tuberculosis. 

The tetrabrom-compound, useful for identification, may be prepared 
by dissolving .5 gram of catechol in 2.5 mils chloroform and adding .4 
mil bromin. The solvent is evaporated, the residue dissolved in 5 mils 
cold alcohol, 20 mils water added, shaken, filtered, washed with 5 mils 
water and the procedure repeated. The resulting product after drying 
on a tile will soften at about 185-187°, melting 192-193°. 

Guaiacol or Methyl catechol, CeH^OH^CHs 

Guaiacol is an important constituent of beechwood creosote, and is 
present in the distillate of other woods as well. Considerable quantities 
are obtained on distilling the heart wood of Guaiacum officinale, Lignum 
Vita?. 

Pure guaiacol is a faintly yellowish, limpid oily liquid with a character- 
istic aromatic odor. Its specific gravity is 1.110 to 1.220 at 15° G, and 
it boils 201 to 207° C, readily soluble in alcohol, ether, glycerin, glacial 
acetic acid, and fairly soluble in water. Its aqueous solution gives an 
emerald-green color with ferric chloride. It acts as a reducing agent in 
alkaline solution. 

Guaiacol when heated with hydriodic acid yields methyl iodide and 
catechol. It has the properties of a weak acid, and its salts are decomposed 
by mineral acids. When potassium guaiacol is heated with methyl iodide, 
it yields methyl guaiacol, C6Hi(OCH3)2, known as veratrol. Veratrol 
is an aromatic liquid which is also obtained by heating veratric acid 
with barium oxide. 

If .1 gram of guaiacol in 1 mil of water is treated with .2 gram of 
picric acid in 5 mils of hot water, shaken and cooled slowly, orange crys- 
tals are obtained which when separated and washed will melt at 86° C. 

The chief use of guaiacol is in remedies for tuberculosis and pneumonia. 
It has antiseptic and antipyretic properties also, but its use for these 
purposes is limited. It is dispensed in capsules and pills and mixed with 



768 ORGANIC SUBSTANCES 

wine and other alcoholic solutions. When used locally it is combined 
with fixed oils and glycerin. It is often combined with hypophosphites 
in elixirs and tablets, and may be anticipated in any proprietary remedy 
advertised for tubercular conditions, malt extract, and cod liver compounds 
especially. Beechwood creosote has perhaps a more general use than pure 
guaiacol, but as this creosote, when medicinally pure, consists of about 
90 per cent of guaiacol, the chemistry of the two may be considered simul- 
taneously. 

Beechwood creosote, and for all intents and purposes guaiacol, will 
be found combined with bismuth subnitrate in tablets, with cerium oxalate, 
Nux Vomica and pepsin, with extracts of Podophyllum, Leptandra, 
Euonymus, and chirata as an intestinal tonic; with cod liver or olive oils 
in tonic capsules, with oil of santal ar.d eucalyptus; and with iodoform, 
eucalyptol, and other antiseptics in oily inhalants. 

Guaiacol has been an attractive body for the chemical manufacturer 
to manipulate and exploit in various combinations. One of these deriva- 
tives, the carbonate, is official in our Pharmacopoeia. 



Guaiacol Carbonate 
OC6H4OCH3 

OC6H4OCH3 



co/ 



The name Duotol is also applied to this substance, which is a white 
crystalline, odorless, tasteless powder obtained by the action of carbonyl 
chloride on sodium guaiacol. It is insoluble in water, slightly soluble 
in glycerin and fixed oils, but dissolves readily in alcohol, ether, and 
chloroform. It melts 84 to 87°. It is saponified by alcoholic potash, and 
on acidulating the guaiacol is freed and may be recovered by shaking 
with ether. An alcoholic solution does not give a bluish-green color with 
ferric chloride. 

Guaiacol Benzoate 
,OCH 3 



CeH4< 

OOCC 6 H 5 

Benzoyl guaiacol or Benzosol is prepared by warming the potassium 
salt of guaiacol with benzoyl chloride and crystallizing the product from 
hot alcohol. 

It forms colorless, minute crystals which melt at 59 to 61° C; they 
are odorless and tasteless or nearly so. It is practically insoluble in water, 
sparingly soluble in ether, but readily soluble in hot alcohol. It contains 
54 per cent of guaiacol. 



ETHEREAL SALTS— PHENOLS 769 

It forms with sulphuric acid a permanent yellow coloration which 
on the addition of acetone assumes a characteristic, brilliant cherry-red 
color, distinguishing it from salol, which gives a yellow color. Ferric 
chloride produces in the benzosol sulphuric acid mixture a violet color, 
changing to green and blue, and on the further addition of nitric acid, 
to orange and green, or of potassium nitrate to green, violet, and yellow. 
When heated with alcoholic potash, the odor of guaiacol is developed. 

Its uses are analogous to those of creosote and of benzoic acid. It is 
said to be useful in incipient pulmonary tuberculosis, as an intestinal anti- 
septic in fermentation, diarrhea, typhoid fever, diabetes mellitus, and as 
a urinary disinfectant in cystitis, etc. 

Guaiacolbenzyl-ester or Brenzcain, 
/OCH3 

X)CH 2 C 6 H 5 

Brenzcain is used as a local anesthetic. It forms colorless crystals, 
melting at 62° C, soluble in alcohol, ether, and fixed oils. Its properties 
in comparison with the other local anesthetics have already been dis- 
cussed in the chapter on Cocain. 

Guaiacol Camphorate, CgHi^COOCeKiOCHs^ 

This body, also called Guacamphol, is employed in certain conditions 
of phthisis, and is crystalline, insoluble in water, but soluble in alcohol 
and chloroform. 

Guaiacol Cinnamate or Styracol 

Styracol is guaiacyl cinnamate, C6H5CH : CH-CO-0-(C6H4'OCH 3 ), 
the cinnamic acid ester of guaiacol. 

It forms colorless, odorless, and tasteless crystalline needles, melting 
at 130° C. It is insoluble in water, but easily soluble in alcohol, acetone, 
chloroform, and benzine. It contains 55 per cent of guaiacol, which is 
split off by the action of alkalies. 

Styracol is an intestinal antiseptic. It is useful in the initial stage of 
tuberculosis, in chronic enteritis, and in intestinal disturbances in general, 
catarrh of the bladder, etc. 

Guaiacol Glycerylether or Guaiamar 
Guaiamar is glyceryl guaiacolate, 

CH3O • C 6 H 4 • 0(CH 2 OH • CHOH • CH 2 ). 



770 ORGANIC SUBSTANCES 

It is a white, crystalline, non-hygroscopic powder, melting at 75° C. 
and having a bitter, aromatic taste. It is soluble in 20 parts of water 
at the ordinary temperature, but dissolves best in warm water; it is solu- 
ble in alcohol, chloroform, ether, and glycerin. Its solutions are neutral 
to test paper. It is decomposed by soluble hydroxides and carbonates 
and by strong acids. 

It is intended to be used as a substitute for guaiacol in cases in which 
the latter is indicated. In the form of ointment it has been recommended 
in acute articular rheumatism. 

Guaiacol Phosphate, (C 6 H r OCH 3 -0) 3 PO 

Guaiacol phosphate is a white crystalline powder, melting 98°, insoluble 
in water and ether, but dissolving in alcohol and chloroform. 

Guaiacol Phosphite, (CAOCHaO)^ 

Guaiacol phosphite melts 77-78° C, and is soluble in water and the 
organic solvents. 

Guaiacol Salicylate 

Guaiacol-salol is guaiacol salicylate, C6H4-OH-CO-0-(C6H4-OCH3), 
the salicylic acid ester of guaiacol, closely related to phenyl salicylate 
(salol) . 

It is a white crystalline powder, tasteless, but having a salol-like odor. 
It is insoluble in water, but soluble in alcohol, ether and chloroform.' It 
melts at 65° C. 

It is decomposed by alkalies and alkaline carbonates with the formation 
of alkali salicylate and alkali guaiacol. The alcoholic solution is colored 
wine red by the addition of ferric chloride, but if the alcoholic solution 
is dropped into a watery solution of ferric chloride a turbidity but no 
coloration is produced. 

Guaiacol Valerate, CeH^OCHs-OCOCA 
Geosote is a colorless or yellowish liquid boiling 265° C. 

Guaiacol Methyl Glycolate — Monotal 

Monotal is CH 2 (0-CH3)-COO.(C 6 H4-OCH3), the methyl-glycolic 
acid ester of guaiacol. 

It occurs as a limpid, colorless oil, of a faintly aromatic odor, easily 
soluble in alcohol, ether, benzol, and chloroform; difficultly soluble in 
water. It is soluble in about 6 parts of olive oil. It boils under 15 mm. 



ETHEREAL SALTS— PHENOLS 771 

pressure at about 156° C. It is split up into guaiacol and methylglycolic 
acid when treated with caustic alkalies. 

Monotal is easily saponified by aqueous or alcoholic solutions of potas- 
sium hydroxide and then gives the reactions characteristic of guaiacol 
and methylglycolic acid. It has a specific gravity of 1.17 to 1.18 at 20° C. 

It is used as an analgesic. 

Potassium Guaiacol Sulphonate. Thiocol 

Thiocol is potassium guaiacol sulphonate, C6H 3 (OH)(OCH3)(KS03) 
1:2:6. 

It is a colorless, crystalline powder, neutral or faintly alkaline, odor- 
less, and having a faint bitter, followed by a sweet taste. It is readily 
soluble in water, slightly soluble in ordinary alcohol, but insoluble in 
absolute alcohol and in ether or oils. Its aqueous solution is not precipi- 
tated by barium chloride; ferric chloride produces an intense violet-blue 
color, which disappears on the addition of ammonia, or of concentrated 
solution of alkali chlorides or sulphates. 

It is used in pulmonary tuberculosis, acute and chronic bronchitis, 
pneumonia, whooping cough, etc. 

Calcium Guaiacolmonosulphonate, Ca(C 6 H 3 OHOCH 3 S03)2 

This salt, also known as guaiacyl, is a bluish-gray powder soluble in 
water and alcohol and used as an anesthetic. 

Methylene diguaiacol or geoform is a condensation product of form- 
aldehyde and guaiacol, and has been described in the chapter on " Alde- 
hydes/' An acetylated compound of geoform is called Euguform. 

Among the compounds of guaiacol and the alkaloids may be mentioned 
.piperidin guaiacolate or guaiaperol, melting 80° C, soluble in water, 
alcohol, and ether; quinin guaiacol bisulphonate or guaiaquin and quinin 
dihydrobromguaiacolate or guaiaquinol. 

Silver eosolate is the silver salt of trisulphoacetylguaiacol, 

C 6 HO • CH3 • OC2H3O • Ag 3 (S0 3 ) 3 , 

an antiseptic substance used in gonorrhea, in the form of an injection or 
in bougies. 

Calcium eosolate, the calcium salt of the same acid, 

Ca 3 (C 6 HO • CH 3 OC 2 H30(S03)3)2, 

is soluble in water and acids, and slightly in alcohol. 

Histosan is a guaiacol-albumin compound soluble in alkaline liquids. 



772 ORGANIC SUBSTANCES 



Creosote Carbonate — Creosotal 



Creosote carbonate is a mixture of carbonic acid esters, analogous to 
guaiacol carbonate, prepared from creosote. 

It is a yellowish, thick, honey-like, perfectly clear and transparent 
liquid, containing 92 per cent of creosote. It is odorless and has a bland 
oily taste. It is insoluble in water, but soluble in alcohol, ether, chloro- 
form, benzene, and in fixed oils. 

The addition of a few drops of ferric chloride solution to the alcoholic 
solution should not cause any change in color. On boiling with potassium 
hydroxide solution the odor of creosote is evolved. 

Creosote carbonate has the same action as creosote, but is claimed to 
be non-toxic and devoid of irritant properties. It is recommended as 
a substitute for creosote for internal exhibition in tuberculosis, pneumonia, 
and as an intestinal antiseptic. 

Creosote phosphate is analogous to guaiacol phosphate, insoluble in 
water and alkalies. 

Creosote phosphite is called Phosphotal, is soluble in alcohol, water, 
and ether. 

Creosote tannate or Tanosal is an astringent antiseptic used for throat 
and bronchial troubles, soluble in water, alcohol, and glycerin, and insolu- 
ble in ether. 

Creosote valerate or Eosote is a colorless or yellowish liquid soluble 
in alcohol and ether. 

Creosote oleate is a yellowish oily liquid soluble in alcohol, ether, and 
chloroform. 

Methylenecreosote or Pneumin is a condensation product of creosote 
and formaldehyde. 

Creosote 

The creosote used for medicinal purposes is a mixture of phenols and 
phenol derivatives, which according to the Pharmacopoeia should be 
chiefly guaiacol and creosol, obtained by purifying a distillate of wood 
tar, chiefly that obtained from birch wood. It is a colorless or yellowish, 
highly refractive liquid with a smoky odor, soluble in alcohol, ether, 
chloroform, fixed and volatile oils, and miscible with considerable water to 
a cloudy liquid. Its saturated aqueous solution gives a transient violet- 
blue color, which soon changes to greenish and brown, with a brown pre- 
cipitate. It gives a reddish precipitate with bromin water. 

It is generally reported by investigators that creosote varies greatly 
in composition. 

Coal-tar creosote commonly consists of that portion of coal tar which 
distills between 200 to 300° together with the residual oils from the manu- 



ETHEREAL SALTS— PHENOLS 773 

facture of crude carbolic acid, naphthalene, and anthracene. It usually 
contains naphthalene, phenanthrene, anthracene, diphenyl, and other 
solid hydrocarbons, carbolic acicl, cresols and other phenols, pyridine 
and other basic substances, and so-called undetermined indifferent oils. 
Hager's test for the detection of coal-tar products in wood creosote is as 
follows: One volume of the sample is agitated in a Mohr's burette with 
3 volumes of diluted glycerol (1 vol. water to 3 vols, absolute glycerol) 
and the mixture allowed to stand until separation has occurred. If the 
creosote is pure the volume will remain unchanged. If reduced the gly- 
cerol layer is withdrawn and the treatment repeated and the volume 
again observed, the residual layer indicating the proportion of real wood 
creosote in the sample taken. The coal-tar products can be detected 
in the first glycerol fraction by filtering, diluting with water, and agitating 
the chloroform. On allowing the separated solvent to evaporate spon- 
taneously, the residue should be tested by shaking a portion with half 
its volume of an ethereal solution of collodion when, in the presence of 
much carbolic acid, the collodion will coagulate to a transparent jelly. 
If a drop of the residue is treated with a few drops of neutral ferric chloride 
in a small porcelain evaporating dish the reagent will assume a fine violet 
coloration. 



Homocatechol Methyl Ester or Creosol 




Creosol is homologous with guaiacol and occurs in that fraction of 
creosote boiling about 220° C. It is colorless when freshly distilled and 
has a vanilla-like odor. It is soluble in alkalies and a solution in strong 
alcoholic potash sets to a mass of needles of the potassium compound. 
It reduces silver nitrate on warming and gives a green color with ferric 
chloride, 



Dimethyl Homocatechol, C 6 H 3 CH 3 (OCH 3 ) 2 

This body also occurs in beechwood creosote. It gives no color with 
ferric chloride and is insoluble in aqueous solutions of alkali hydroxides. 



774 ORGANIC SUBSTANCES 

Catechol Monoethyl Ester 
/OC2H5 

X)H 

This substance is closely related to guaiacol and is called Guaethol 
and also, though illogically, guaiacol ethyl. The last term is erroneous 
and confusing because it is not ethyl guaiacol. 

It is a colorless crystalline mass melting at 27 to 28° C, or an oily 
almond-colored liquid, with a pleasant aromatic odor. It boils at about 
215° C, dissolves in alcohol, ether, and chloroform, but is insoluble in 
water. 

It is used for the same purposes as guaiacol. 

Resorcinol 

Resorcinol or meta-dihydroxybenzol has been recommended for a 
number of ailments, but its largest use is probably for aiding the removal 
of dandruff, and hence its presence may be expected in hair tonics and 
other mixtures designed to improve the condition of the scalp. Hair 
tonics may contain in addition to resorcinol, quinin, cantharides, extract 
of sage, precipitated sulphur, lead acetate, beta-naphthol, glycerin, and 
alcohol. 

Resorcinol is also used internally for asthma, hay fever, seasickness, 
whooping cough, diphtheria, etc., where remedies of an antiseptic, anti- 
pyretic, or antizymotic action are indicated. It is also applied in inflam- 
matory conditions of the mucous membrane of all parts of the 'body, 
and in erysipelas. 

It will be found in tablets with sodium bicarbonate and borax, and in 
ointments combined with other antiseptic agents. 

When pure, resorcin is a white crystalline substance, but on standing 
and especially on exposure to the light, it turns reddish. It melts 109- 
111°, dissolves easily in water, alcohol, and ether, slightly in chloroform, 
benzol, and carbon bisulphide. Its aqueous solution gives a dark-violet 
color with ferric chloride, and a crystalline precipitate of tribromresor- 
cinol with bromin water, but no precipitate is given by lead acetate. It 
reduces ammoniacal copper and silver salts. When fused with phthalic 
anhydride the melt dissolves in sodium hydroxide with a beautiful green 
fluorescence due to the formation of a fluorescein. This reaction is 
characteristic of other meta-dihydric phenols. 

The trinitro-compound prepared as described under Thymol melts 
175°; .1 gram resorcinol when boiled with 1 mil of potassium hydroxide 
to which a drop of chloroform is added develops a crimson color. 

A solution of resorcinol mixed with copper sulphate and sufficient 



ETHEREAL SALTS— PHENOLS 775 

ammonia to redissolve the precipitate first produced, yields a deep black 
liquid which dyes wool and silk black. 

Resorcinol may be shaken out of its solution in ether by using dilute 
alkali, and on acidulating the latter, the resorcinol may be recovered by 
ether. In the general scheme of analysis it will appear when a residue 
left by shaking the aqueous acid solution with ether, is examined and it 
may be identified by applying the reactions above described. 

CM. Pence 1 has made a study of the methods of estimating resor- 
cinol, and recommends the following for assaying the commercial article: 
1.4563 grams of the sample are dissolved in water and made up to 500 
mils in a graduated flask. A 25-mil portion is transferred to a 500-mil 
glass-stoppered flask, 50 mils N/10 bromin added, 50 mils water and 
5 mils concentrated hydrochloric acid, the mixture shaken and allowed 
to stand for one minute; 200 mils of water are then added, 5 mils of 20 
per cent potassium iodide and after five minutes the liberated iodin is 
titrated with sodium thiosulphate. The number of mils of N/10 bromin 
solution consumed divided by .4 gives the percentage of resorcinol. A 
blank is run using 7 to 10 mils of potassium iodide. 

A mixture obtained by melting together equal parts of resorcin and 
iodoform is sold under the name of " Resorcinol." It is an amorphous 
brown powder, with an iodin odor, and is used as an antiseptic in oint- 
ments and dusting powders. 

Potassium diiodoresorcinol monosulphonate, C6Hl2(S03K)(OH)2, is 
used as an antiseptic under the name " Picrol." 

Resorcinol Monacetate or Euresol 

/OH 
C 6 H4< 



\)COCH3 



Euresol is a thick, yellowish, oily liquid with an agreeable odor, boiling 
283° C. It is soluble in acetone and in alkaline solutions, and is used in 
the treatment of chilblains, acne and as a substitute for resorcin in external 
application. 

Fluorescein 

Resorcinolphthalein— O : (C 6 H 3 OH) 2 : C-Cel^-COO. 

Fluorescein is prepared by the fusion of phthalic anhydride and resor- 
cinol at 195 to 200° C. till the mass becomes solid. This is extracted with 
water and the residue dissolved in potassium hydroxide solution, which 
is then filtered and the fluorescein precipitated with acid. 

It is an orange red powder, insoluble in water, ether, chloroform, and 
benzol; soluble in hot glacial acetic acid and boiling alcohol. It dissolves 
in alkaline solutions with formation of salts. 

1 J. Ind. and Eng. Chem., 1911, 3, 820. 



776 ORGANIC SUBSTANCES 

The alkaline solution by transmitted light is red; by reflected light 
it has a green flourescence even in very dilute solutions. When fluore- 
scein is boiled with chalk water, the calcium salt of fluorescein is formed 
which is recognized by its red-brown color and green sheen. 

The soluble sodium salt of fluorescein has been used for the diagnosis 
of corneal lesions and detection of minute foreign bodies imbedded in 
the cornea. 

Resorcinol-salol and resorcinol-eucalyptol are antiseptics. Resor- 
cinol-hexamethylenetetramine or Hetralin is used in gonorrhea and 
cystitis. 

Resorcmol is combined with mercury in a substance called mercury- 
resorcinol acetate, a yellow crystalline powder, soluble in alkalies and 
strong acids, and used as a hypodermic in syphilis, and in ointment form 
for local application. 

Resaldol 

Resaldol is the acetyl derivative of a condensation product of chlor- 
methylsalicylic aldehyde and resorcin. It is a yellow, amorphous, light 
powder insoluble in water, but soluble in alkalies. It is used as an intes- 
tinal antiseptic. 

Hydroquinone 

Hydroquinone, though used to a slight extent as an antiseptic and 
antipyretic, is best known as a photographic developing agent. Its 
most important feature in connection with drug chemistry is its relation 
to the glucosides and its appearance as a product of the hydrolysis of 
these principles. It is one of the products of the hydrolysis of arbutin. 

It forms colorless crystals, melting 169° C, dissolving easily in alcohol 
and ether and less readily in water. When its aqueous solution is treated 
with ferric chloride, fine green metallic crystals of quinhydrone, 
C6H402-C6H4(OH) 2 , appear, which can be crystallized pure out of boiling 
water. This substance dissolves in alcohol and ether to a yellow-colored 
solution and in ammonia to a green, which turns brown on exposure to 
the air. 

Hydroquinone-dimethyl ester, melting 56° C, is formed by boiling 
hydroquinone under pressure with methyl iodide and potassium hydroxide. 

Dihydroxytoluol or Orcinol 

/CH 3 1 

CeHs^-OH 3 

X)H 5 

Orcinol occurs in many lichens, probably combined in complex acid 
or glucosidic combinations, and is freed on hydrolysis. It has been 



ETHEREAL SALTS— PHENOLS 777 

obtained from some of the well-known vegetable colors, litmus, cudbear, 
and archil, and recovered from the alkaline fusion of aloes. It has a limited 
use as an antiseptic in skin diseases. Orcinol forms colorless crystals 
containing 1 molecule of water, which redden on exposure. It has a 
sweet but unpleasant taste. The crystals melt at 58-59° C, and lose 
all the water of crystallization below 100°. It dissolves readily in water, 
alcohol, and ether and the aqueous solution gives a violet color with ferric 
chloride. 

It forms a crystalline compound with ammonia, and when its ammonia- 
cal solution is exposed to the air it absorbs oxygen, giving a purple solu- 
tion from which acetic acid precipitates a red coloring matter called orcein. 
The new substance is sparingly soluble in water unless alkaline, but dis- 
solves in alcohol to a purple solution which is turned red by acid. 

Maltol, C 6 H 4 0(OH) 2 

Maltol is a phenolic body which occurs naturally and which was for 
a long time confused with salicylic acid in testing for preservatives in 
malt liquors. It is difficultly soluble in cold water and benzol, but dis- 
solves easily in hot water, ether and alkalies, and is precipitated from the 
latter by carbon dioxide. Its aqueous solution gives a violet color with 
ferric chloride, reduces Fehling's solution and ammoniacal silver oxide. 
It does not, however, respond to test of Jorissen for salicylic acid, by which 
a red color is developed in the presence of this acid when 4 to 5 drops of 
10 per cent potassium nitrite, 4 to 5 drops 50 per cent acetic acid and 1 
drop of 10 per cent copper sulphate are added and shaken with the 
suspected sample. 

Maltol appears to be a reaction product resulting from the carameli- 
zation of carbohydrates. 

Trihydric Phenols 

The type compound of this group exists in three isomeric forms, all 
of which are well known bodies : 

OH OH OH 

/\)H (Aj /\ H 

OH Hol JoH 



OH 

Pyrogallol Phloroglucinol Hydroxyhydroquinone 

Pyrogallol 

Pyrogallol, called pyrogallic acid by the photographers, is used as an 
antiseptic in skin diseases. It may be obtained by heating gallic acid 



778 ORGANIC SUBSTANCES 

with 2\ parts of water to 210° in an autoclave, or with glycerin to 195° 
until the evolution of carbon dioxide ceases. 

It crystallizes in fine needles, melting 132° C, boiling 210°, very solu- 
ble in water, alcohol, and ether, and turning brown and black in presence 
of alkaline solutions due to the rapid absorption of oxygen. Its aqueous 
solution gives with ferric chloride a red, and with ferrous sulphate con- 
taining a trace of ferric chloride a deep-blue solution. 

Pyrogallol has powerful reducing properties, precipitating silver and 
gold in the metallic state, and therefore being of value in photography, 
and as a hair dye. When heated with phthalic anhydride it yields gallein, 
which is used as a red dye, the alkaline solution being rose-red. (Blue, 
Allen.) 

When acetylated it yields triacetylpyrogallol, a substance known as 
Lenigallol, melting 165° C, insoluble in water, and dissolving in alkalies 
with decomposition. Lenigallol is used in psoriasis, eczema, and other 
skin diseases. 

A monoacetate is marketed as Eugallol. Both of these may be saponi- 
fied by alkalies, setting free pyrogallol, which of course is soon oxidized. 

Saligallol is said to be pyrogallol disalicylate. It is marketed in acetone 
solution. 

An oxidized pyrogallol is sold as a remedy for skin diseases. 

Phloroglucinol 

Phloroglucinol is intimately associated with the chemistry of some of 
the glucosides and resins. It results from the hydrolysis of phloridzin, 
a glucoside of the bark of the apple tree, and on fusing with potash, gam- 
boge, dragon's blood, kino, catechin, fustic, etc. 

In order to obtain it from the gums they are fused with potassium 
hydroxide until the melt is quiet, the mixture dissolved in water, acidified 
with sulphuric acid, and shaken with ether, which removes the phloro- 
glucinol and protocatechin or other acid resulting. After evaporating 
the ether, the residue is dissolved in water, the acid precipitated with a 
little lead acetate, the excess of lead removed by hydrogen sulphide and 
the phloroglucinol again extracted with ether. 

When resorcinol is fused with sodium hydroxide phloroglucinol results. 

It crystallizes in colorless prisms with two molecules of water which 
may be entirely driven off at 100°. The anhydrous body melts 218-220° 
but a specimen will often begin to melt at 200° if heated slowly. It sub- 
limes easily, is readily soluble in water, to which it imparts a sweet taste, 
and dissolves easily in alcohol and ether. Its aqueous solution is colored 
bluish violet by ferric chloride. It reduces Fehling's solution. Its solu- 
tion in hydrochloric acid stains wood violet-red. Its alkaline solutions 
rapidly turns brown in contact with air owing to absorption of oxygen. 



ETHEREAL SALTS— PHENOLS 779 

A cold solution of phloroglucinol in acetic acid reacts with potassium 
nitrite to form the trinitrosophloroglucinol, which separates on addition 
of potassium hydroxide and alcohol in the form of its potassium salt, a 
green, crystalline, explosive body. 

Phloroglucinol, when dissolved in sulphuric acid and added to a mix- 
ture of nitric and sulphuric acids, yields the tri-nitro derivative melting 
165 to 166° C. It is a yellow, explosive body which dyes wool and silk 
yellow. 

When digested with acetyl chloride it yields the triacetyl derivative, 
melting 106°. By the .phthalein fusion it gives a blue color on adding 
alkalies. 

While in most of its reactions phloroglucinol behaves as symmetrical 
trihydroxy benzol, it also acts like a triketone, as it gives a trioxime, 
CeH6(NOH)3, with hydroxylamine. It is possible that it exists in tauto- 
meric forms, the second being represented by 



H 5 




H 2 



1° 
O 



a triketone of hexamethylene. 

Phloroglucinol will be found occasionally in medicines intended for 
antiseptic, antipyretic, and tonic purposes. 



Hydroxyhydroquinone 

This phenol is prepared from pyrogallol by fusion with potash pre- 
cisely as phloroglucinol is obtained from resorcinol. It melts 140°, is 
readily soluble in water, and its aqueous solution is colored greenish brown 
by ferric chloride, changing to blue and red on adding sodium carbonate. 



THE NAPHTHOLS 

Alpha- and beta-naphthol are monohydroxy derivatives of naphthalene 
and correspond with the monohydric phenols. Their properties are in 
many respects similar to those of the phenols; they dissolve in alkalies, 
forming metallic derivatives which are decomposed by acids and carbon 
dioxide, and yield acetyl and alkyl derivatives on the hydroxyl group. In 
other ways, however, the hydroxyl group is shown to be more sensitive 
than in the phenols, for heating with ammonia-zinc chloride to 250° the 



780 ORGANIC SUBSTANCES 

corresponding amido compound is produced, the same reaction with 
phenol requiring a much higher temperature, and when heated with an 
alcohol and hydrogen chloride alkyl derivatives result. 

Both a- and /3-naphthol are of medicinal importance, but the latter and 
its derivatives have probably the most extensive use. They are anti- 
septic and germicidal in action and are used in ointments and washes in 
skin diseases, and internally are employed in the treatment of typhoid 
fever, chronic diarrhea, smallpox, scarlet fever, measles, etc. Alpha- 
naphthol is reported to be somewhat more powerful and weak solutions are 
credited with preventing the development of the spores of the tubercle 
bacilli. 

Alpha-naphthol is a colorless crystalline substance with a faint phenol 
odor, melting 94°, boiling 278-280° C, readily soluble in alcohol and 
ether, but sparingly only in hot water. Its aqueous solution gives a scanty 
white or purplish-white precipitate with ferric chloride or a reddish color 
turning violet. 

It is readily acted on by nitric acid, yielding a dinitro derivative, 
CioH5(N02)2-OH, which crystallizes in yellow needles, melting at 130°, 
possessing marked acid properties, decomposing carbonates and "forming 
deep yellow salts which dye silk a golden yellow. The sodium compound, 
CioH 5 (N02)20Na+H 2 0, is known as Martius yellow. 

When .5 gram of alpha-naphthol is dissolved in 10 mils of 1 per cent 
sodium hydroxide and boiled for one-half minute with 5 drops of chloro- 
form a blue color appears, changing to bluish green and on standing four 
to five hours to a yellow green. 

If .1 gram is mixed with .15 gram of picric acid and treated with 10 
mils of boiling dilute alcohol (1 : 1) a picrate is formed, which when filtered, 
washed and dried on a porous plate melts on rapid heating at 188.5 to 
189.5° C. 

An aqueous solution of calcium hypochlorite gives a dark violet color 
changing to reddish brown. 

Beta-naphthol forms colorless laminae, melting 122° and boiling 285-6° 
C, soluble in alcohol, ether, chloroform, and fixed oils, but only slightly in 
cold water. Its aqueous solution gives an opalescence with ferric chloride 
or a pale-green tint. Its picrate, prepared as above, melts 155.5 to 156.8° 
C. When boiled with sodium hydroxide and chloroform a blue color is 
obtained which fades rapidly. 

Calcium hypochlorite in aqueous solution gives a pale yellow color, 
destroyed on adding excess of the reagent. 

Reuter has described a test for distinguishing between naphthalene 
and the two naphthols, using chloral hydrate as a reagent: One-tenth 
gram of the sample is mixed with 2.5 grams chloral hydrate and warmed for 
ten minutes; and simultaneous tests are run using in addition 5 drops 



ETHEREAL SALTS— PHENOLS 



781 



of strong hydrochloric acid in the one case and the same amount of acid 
and a piece of zinc in the other. The results are as follows: 







Naphthalene 


a-Naphthol 


/3-Naphthol 


Chloral Hydrate 




Colorless 


Ruby red, trans- 
parent, not flu- 
orescent 


Pure blue, trans- 
parent, not flu- 
orescent 


Chloral Hydrate 


+HC1 


Very slight pink 


Intense dark 
greenish blue, 
not transparent 


Intensely yellow, 
transparent 


Chloral Hydrate 


+HCl+Zn 


Violet to brown 


Dark violet blue. 
Water throws 
out a violet floc- 
culent precipi- 
tate. Alcohohc 
solution violet 
with fluores- 
cence 


Dark brown. 

Water throws 
out a greasy pre- 
cipitate. Alco- 
holic solution 
yellow with blue 
fluorescence 



When a small quantity of the sample is treated with 2 mils of iodin 
in potassium iodide and an excess of sodium hydroxide added, alpha- 
naphthol gives a turbid liquid of an intensely violet coloration, and beta- 
naphthol a clear colorless liquid. 



Estimation of Beta-Naphthol 

Kuster x recommends digesting a weighed quantity of the sample in 
a sealed flask with reduced pressure, on a water-bath with a measured 
quantity of a saturated aqueous solution of picric acid. The naphthol 
is converted quantitatively into an insoluble picrate and the amount of 
picric acid remaining in solution is ascertained by titrating an aliquot 
portion with N/10 barium hydroxide. The picrate formed is slightly 
soluble in water, so that it is necessary to allow .0075 gram of beta- 
naphthol per 100 mils of the picric acid solution used. 

Messinger and Vortmann's iodometric method for determining phenols 
has been adapted to beta-naphthol. Three grams of the sample are dis- 
solved in a solution of not less than 3.5 grams sodium hydroxide and diluted 
to a known volume, not less than 250 mils. A 10-mil aliquot is placed in 
a small flask, heated to 55° C. and N/10 iodin added until the solution 
shows a yellow color. A greenish precipitate will settle on shaking. The 
cooled liquid is acidified with dilute sulphuric acid, made up to 250 mils 
and an aliquot titrated with sodium thiosulphate. The figure for the 

iBer., 1894,27, 1101. 



782 ORGANIC SUBSTANCES 






iodin actually used calculated to the whole amount taken and multi- 
plied by .3784 will give the amount of beta-naphthol present. 

Alphol 

Alphol is the salicylic ester of alpha-naphthol, C6H4(OH)COOCio07. 
It is a reddish-white crystalline powder, melting 83° C, insoluble in water, 
but soluble in alcohol, ether, and fixed oils. It is used as an antiseptic 
and antirheumatic. 

Most of the naphthol derivatives which are encountered in practice 
are of beta-naphthol. 

Alumnol 

Aluminum Beta-naphthol-Disulphonate, A^CioHs- OH -(803)2)3, the 
aluminum salt of beta-naphthol-disulphonic acid. 

It forms a fine, nearly white, non-hygroscopic powder, soluble in 1.5 
parts of water, forming a faintly acid and slightly fluorescent solution. 

It is easily soluble in glycerin, but sparingly soluble in alcohol and 
insoluble in ether. When dried it loses about 9 per cent of water, and 
when exposed to the air it is darkened in consequence of its reducing prop- 
erties. It is precipitated from solution by albuminous and gelatinous 
bodies, but these precipitates are redissolved in excess of the latter bodies. 

The dried compound should yield 12.7 per cent of ash (alumina) on 
incineration. It is an astringent and mild antiseptic. 

Beta-Naphthol Benzoate, C 6 H 5 • COO • Ci H 7 

It forms colorless needles, or a white crystalline powder, colorless and 
tasteless, melting at 110° C. It is almost insoluble in water, but readily 
soluble in alcohol and in ether; also soluble in chloroform, in glycerin 
and in olive oil. 

It is decomposed by heating with caustic alkalies into naphthol and a 
benzoate which will then give their characteristic reactions. 

To test beta-naphthol benzoate for the presence of beta-naphthol it 
should be shaken several times with dilute solution of sodium hydroxide 
(1 : 10) and immediately filtered. If beta-naphthol is present in con- 
siderable amount it will separate as a turbidity or precipitate after acidify- 
ing with dilute sulphuric acid. If the amount of beta-naphthol is small 
no precipitate appears, but the alkaline solution shows a bluish fluor- 
escence and if it is boiled with chloroform a green color is produced. 

It is used internally as an intestinal antiseptic in diarrhea and typhoid 
fever. Externally it is said to be useful as a parasiticide in the form of 
3 to 10 per cent ointment. 



ETHEREAL SALTS— PHENOLS 783 

Betol 

Naphthalol — Naphthol-Salol— Salinaphthol. Betol is beta-naphthyl 
salicylate, C6H4 • OH • CO • • (C10H7) , the salicylic acid ester of beta- 
naphthol. 

It is a white, shining crystalline powder, colorless and tasteless, melting 
at 95° C. It is insoluble in cold or hot water or glycerin, difficultly soluble 
in cold alcohol or turpentine, easily soluble in boiling alcohol, in ether, 
in benzene, and in warm linseed oil. In the cold it is not changed by 
acids or alkalies of moderate concentration. When heated with alkalies 
it is decomposed into its constituents, which, if the solution is acidulated, 
will crystallize. 

It is distinguished from salol by its higher melting-point and by the 
production of a brownish-green color, when a trace of nitric acid is added 
to its yellow-colored solution in pure sulphuric acid. 

Bismuth Beta-Naphtholate 

Bismuth beta-naphtholate occurs in the form of a brownish or grayish 
powder without odor, almost tasteless and insoluble in water. It is slightly 
soluble in alcohol. 

From 1 to 2 grams of bismuth beta-naphtholate is shaken in a separator 
during one hour with 25 mils of chloroform and 25 mils of concentrated 
hydrochloric acid, and then 50 mils of water added and the mixture again 
shaken. The chloroform solution is then drawn off and the acid mixture 
extracted with three more portions of 10 mils each of chloroform and the 
combined extracts evaporated and dried to constant weight over sulphuric 
acid. A residue should remain, weighing at least 15 per cent of the material 
used, which should respond to tests of identity for beta-naphthol. 

If bismuth beta-naphtholate is examined by the method given below, 
the bismuth oxide found should weigh not less than 60 per cent of the 
material taken. 

The acid solution from which the naphthol has been extracted is trans- 
ferred to a beaker, diluted to 200 mils, heated to boiling, ammonia water 
added till turbidity appears, then sufficient hydrochloric acid to clear up 
the turbidity, and then 50 mils of 10 per cent ammonium phosphate solu- 
tion is added to the boiling liquid. The precipitate is allowed to subside, 
the clear liquid decanted through a tared porcelain Gooch crucible, the 
precipitate washed with hot water by decantation and finally transferred 
completely to the crucible. The precipitate and crucible are dried, placed 
in a nickel crucible, and exposed to the full heat of a Bunsen flame till the 
weight is constant. The weight of the resulting bismuth phosphate multi- 
plied by .6869 should yield a figure (representing bismuth, Bi) equal to 
not less than 60 per cent of the material taken. 



784 ORGANIC SUBSTANCES 

It is used in catarrhal and fermentative gastroenteric disorders, such 
as gastritis, dysentery, and diarrhea. 

Diiodobetanaphthol, CioH 6 I 2 2 

Iodonaphthol or naphtholaristol is a yellowish-green powder which 
decomposes on heating with evolution of violet fumes. It is insoluble in 
water, and only slightly in alcohol and ether, but dissolves readily in 
chloroform. 

Betanaphthol Lactate 

This substance, known as Lactol, is used as an antiseptic. 

Sodium betanaphtholate is called Microcidin, and is employed as a 
constitutent of surgical dressings, and in antiseptic sprays for nose and 
throat diseases. 

The naphthols combine with sulphuric acid to form a series of sulphonic 
acids. 

The calcium salt of beta-naphthol sulphonic acid is called Abrastol 
or Asaprol, a reddish-white powder, soluble in water and alcohol, and 
decomposing at about 50° C. It has antiseptic, analgesic, and antipyretic 
properties and may be found occasionally in medicinal analysis. 

Detection of Abrastol. — Sinibaldi's Method. — Make 50 mils of the 
sample alkaline with a few drops of ammonium hydroxide and extract 
with 10 mils of amyl alcohol (ethyl alcohol is added if an emulsion is 
formed) . Decant the amyl alcohol, filter if turbid, and evaporate to dry- 
ness. Add to the residue 2 mils of a mixture of equal parts of strong 
nitric acid and water, heat on the water-bath until half of the water is 
evaporated, and transfer to a test-tube with the addition of 1 mil of water. 
Add about .2 mil of ferrous sulphate and an excess of ammonium hydroxide, 
drop by drop, with constant shaking. If the resulting precipitate is of 
a reddish color, dissolve in a few drops of sulphuric acid, and add ferrous 
sulphate and ammonium hydroxide as before. As soon as a dark-colored 
or greenish precipitate has been obtained introduce 5 mils of alcohol, dis- 
solve the precipitate in sulphuric acid, and shake the fluid well and filter. 
In the absence of abrastol this method gives a colorless or fight-yellow 
liquid, while a red color is produced in the presence of .01 gram of abrastol. 

There are several phenols or phenol ethers occurring in essential oils 
which are in somewhat close realtionship, as they are all either allyl or 
propenyl derivatives of benzol. They usually have characteristic odors 
different in each case, and are the main ingredients identifying the par- 
ticular oils in which they occur. It is impossible to describe these odors, 



ETHEREAL SALTS— PHENOLS 785 

but when one becomes familiar with them they furnish the best evidence 
of their presence, and unless one is dealing with a straight oil, or has a 
sufficiently large sample, -this odor is the best and often the only means 
of identification. 

Chavicol, C 6 H 4 (CH 2 CH = CH 2 )OH, 1-4 

Chavicol is a colorless liquid boiling about 237° with specific gravity 
1.033 at 18°, occurring in bay and betel leaf oils. Its aqueous solution 
gives a deep-blue color with ferric chloride. 

Methyl Chavicol, C 6 H 4 (CH 2 CH = CH 2 )OCH s , 1-4 

Methyl chavicol is a colorless liquid with a faint anise-like odor, boiling 
215-216° C, sp. gr. .9714 to .972 at 15° C. It occurs in the oils of anise, 
star anise, fennel, bay, and basil oils. It is isomeric with anethol, which 
is the propenyl derivative, and may be converted to anethol by boiling 
with alcoholic potash. Estragol is also isomeric with methyl chavicol 
and occurs in tarragon oil. 

Anethol, C 6 H 4 (CH = CHCH3)OCH 3 , 1-4 

Anethol, or paramethyxypropenylbenzene, is also called anise cam- 
phor. It is a white crystalline substance with a strong anise-like odor, 
melting 21° C, boiling 233-234°, sp. gr. .985 to .986 at 21 to 25° C. It 
gives a well-defined bromin compound monobrom anethol dibromide, 
which melts 107 to 108° C. Anethol is the chief constituent of anise and 
star anise oils and is present in fennel. 

Safrol, C 6 H 3 (CH 2 CH = CH 2 )OOCH 2 , 1-3-4 

Safrol is the methylene ester of allyl pyrocatechol and is a colorless 
or faintly yellow liquid with a characteristic odor of sassafras. It boils 
233°, sp. gr. 1.108 at 15° C, and on cooling yields crystals which melt 
at 11° C. When oxidized with chromic acid piperonal (heliotropin) and 
piperonylic acid C 6 H 3 OOCH 2 • COOH result. 

Safrol is the characteristic and chief component of sassafras oil, and 
occurs in camphor oil. It has some use in medicine as a tonic, aromatic, 
and carminative. 

By proper treatment it is transformed into the propenyl derivative 
isosafrol, C 6 H 3 (CH = CH-CH3)OOCH 2 . 

Eugenol, C 6 H 3 (CH 2 CH = CH 2 )OCH 3 OH, 1, 3, 4 

Eugenol is paraoxymetamethoxyallylbenzene, and is also called eugenic 
or caryophyllic acid. It is a faintly yellow liquid with the odor of cloves, 



786 ORGANIC SUBSTANCES 

it boils 252° at 749 mm., sp. gr. 1.072 at 15°. Its alcoholic solution gives a 
bluish-green color with ferric chloride, but it gives only a transient grayish 
green in aqueous solution. Upon oxidation it yields vanillin and vanillic 
acid, and when treated with benzoyl chloride a benzoic ester is produced 
which melts 69-70° C. 

Isoeugenol, boiling 260° C, the propenyl derivative, results on molec- 
ular rearrangement by boiling with alcoholic potash. Isoeugenol gives 
a blue-green with ferric chloride. Eugenol is soluble in alkalies and when 
shaken with ammonia is converted into a yellow crystalline mass. 

A drop of concentrated sulphuric acid added to 10 drops of eugenol 
produces a blue color changing to purple on adding more acid. 

Eugenol is an important constituent of clove oil and is also found in 
many others, including cinnamon, sassafras, pimento, bay, camphor, etc. 
It has antiseptic properties and is used as an ointment in skin diseases 
and tubercular affections and as an antiseptic in dentistry. 

Methyl Eugenol, C 6 H 3 (CH 2 CH = CH 2 )(OCH 3 )(OCH 3 ), 1, 3, 4 

Methyl eugenol has a less powerful though similar odor to eugenol, 
and boils 248-249°. It gives a bromin derivative melting 78° and on 
oxidation with permanganate is converted into veratric acid, melting 
179-180°. It occurs in bay, citronella, hazelwort, paracoto bark, and other 
oils. 

Eugenoform 

Eugenoform is the sodium salt of a product obtained by the action 
of. formaldehyde on eugenol. It forms colorless crystals soluble in water 
and alcohol and is used as an intestinal antiseptic in cholera and typhoid 
fever, and as a disinfectant. 

Eugenol Benzoate 

Benzoeugenol forms white crystals melting 68-70° C, soluble in alcohol, 
ether, and chloroform and is used in tuberculosis and for neuralgia. 

Eugenol Cinnamate 

The ester, melting 90°, forms odorless and tasteless shining needles 
soluble in ether, chloroform, and hot alcohol. It is used as an antiseptic 
in tuberculosis. 

Asarol, C 6 H 2 (CH = CHCH 3 )(OCH 3 )3 

Ararol, asaronic, or asarum camphor, is propenyl trimethoxy benzene 
and occurs in the oils of hazelwort (Asarum europeum) and matico. It 
is an emetic and cathartic. 

Asarol melts 62° and yields a dibromide melting 85-86° C. 



ETHEREAL SALTS— PHENOLS 787 



Apiol, C 6 H(CH 2 • CH = CH 2 ) (OCH 3 ) 2 OOCH 2 

Apiol or parsley camphor is obtained from oil of parsley seed, Petro- 
selium sativum, in which it occurs to the amount of about 25 per cent. 
It also occurs in the oil of the seeds and roots of celery, Apium graveolens. 
It crystallizes from ether, melting 36° and boils 294°. It is insoluble in 
toater but dissolves in alcohol, ether, fixed, and volatile oils. Oxidizing 
agents convert it to apiol aldehyde, and on prolonged treatment to apiolic 
acid. By the action of nitric acid it is partially converted to oxalic acid 
and partly to a crystalline yellow nitro compound melting 116° C. Bro- 
min in carbon bisulphide acts on apiol to produce tribromapiol, which 
may be crystallized out of alcohol, melting 88° C. 

Commercial apiol has an oily consistency and is of varying composi- 
tion. It is used as an emmenagogue and antiperiodic and is dispensed 
in capsules and in oily solutions, usually olive oil. Celery is used in 
dropsy and rheumatism and to a large extent in nerve tonics. 

When apiol is boiled with alcoholic potash it is converted into isoapiol, 
the propenyl derivative, melting 56° and boiling 304°. It occurs in dill 
camphor. 

Saligenin, C 6 H 4 OHCH 2 OH 

Saligenin is ortho-oxybenzyl alcohol and has the characters of both a 
phenol and an alcohol. It is one of the products of the hydrolysis of 
salicin, and can be prepared synthetically from carbolic acid and form- 
aldehyde. It forms colorless to yellowish crystals, melting 86°, subliming 
100°, soluble in alcohol, ether, and hot water. Its alcoholic solution 
gives a reddish- violet color with ferric chloride changing to yellow. With 
concentrated sulphuric acid a red color is produced. When boiled with 
anilin, oxybenzyl anilin is produced, melting 108°. 

Saligenin is chiefly important as a means of identifying salicin, but it 
is also used to a slight extent as an antirheumatic. 

Homosaligenin, C 6 H 3 • CH 3 CH 2 OH • OH, 1, 2, 4 

Homosaligenin melts 105°, gives a blue color with ferric chloride, and 
on boiling with dilute hydrochloric acid yields homo-saliretin, melting 
200-205° C. 

Diosphenol and Buchu 

The leaves of Barosma betulina (Rutacese) are recognized as the 
official buchu. The therapeutic value of the drug is due probably to 
an essential oil, which contains as its chemically recognizable constituent, 
a phenolic and ketone-like body called diosphenol. The same or closely 
allied oil is present in the leaves of B. crenulata, which, however, is con- 



788 ORGANIC SUBSTANCES 






sidered an adulterant of official buchu. It would be impossible, however, 
to detect the difference between these drugs in the extract form, the state 
in which they occur in medicinal preparations. 

Buchu is valuable chiefly as a diuretic and is usually combined with 
some other kidney stimulant such as Juniper berries, potassium nitrate, 
triticum, and cornsilk. It will be found in many of the proprietary 
remedies recommended for kidney troubles, and is a constant component 
of kidney pills, and is often present in the trick pills containing methylene 
blue, which are used to deceive the unwary regarding the condition of 
their urine. 

Liquid preparations contain buchu combined with juniper berries, 
cubeb, uva ursi, and nitrous ether; with juniper berries and potassium 
acetate; with Collinsonia, juniper berries, and Pareira; and small quan- 
tities of buchu are present in the " Buchu Gins " which used to be widely 
sold as medicinal beverages. Extract of buchu is present in cystitis pills 
combined with boric acid, triticum, cornsilk, Hydrangea, atropin, and 
potassium bicarbonate or benzoic acid, or Viburnum prunifolium. It 
is also combined with Hyoscyamus and potassium bicarbonate; and 
with Digitalis, squill, and potassium nitrate; and is present in certain 
capsule formulas combined with cubebs and copaiba. 

In commerce round and long buchu leaves are distinguished; the first 
are those of B. betulina and B. crenulata; the second those of B. serrati- 
folia. 

E. M. Holmes reports the finding of three different species of leaves 
which clpsely resemble official buchu, and which might functionate as 
adulterants. The chief points of difference are as follows: Empleurum 
serrulatum, leaves acutely jointed, no gland at apex, odor different, and 
fruit consists of a single follicle with a sword-shaped beak: Barosma 
echloniana, leaves with rounded base, broader in proportion, thickened 
margin with very shallow crenulations, no gland at the very obtuse apex 
and a peculiar dull surface, the flowers have about six purplish glands 
on each petal: Psoralia obliqua, oblique or unequal sided lamina, recurved 
apiculus, veins hairy, and difference in structure of the oil glands. 

The leaves of B. betulina yield on distillation from 1.3 to 2 per cent 
of oil, and from this the characteristic principle diosphenol separates on 
standing. The oil has a camphoraceous and mint-like odor. Diosphenol 
is called buchu camphor. 

It is a colorless crystalline substance meiting 82°, boiling 232°, or at 
112° under 14 mm., and has the properties of both a phenol and a ketone. 
It may be extracted from oil of buchu by alkalies, from which it is repre- 
cipitated by acids, and forms an oxime and hydrazone. It gives a dark- 
green color with ferric chloride. 

The presence of buchu is usually apparent by its characteristic odor. 



ETHEREAL SALTS— PHENOLS 789 

This odor and the identification of the diosphenol in preparations contain- 
ing appreciable quantities of buchu are the only means at present for identi- 
fying the drug. The odor should, of course, be compared with that evolved 
by a known sample. When the sample under examination is a pill or 
tablet, the characteristic constitutents of buchu can be separated by 
grinding, macerating with water, and subjecting to steam distillation. 
The distillate will contain the essential oil of buchu recognizable by its 
odor and on shaking with ether this will dissolve. From the ethereal 
solution the diosphenol can be shaken out with alkali, and recovered by 
acidulating and extracting with ether. Juniper oil will appear in the 
distillate if present originally in the sample and if in large amount may 
disguise the buchu, but the procedure for separating the diosphenol will 
eliminate the juniper constituents and enable one to detect the buchu, 
provided there is enough of it present. 

Detection of Diosphenol 

Make about 300 mils of the liquor distinctly acid and distill, taking 
off three fractions of about 100 mils each. Saturate the third fraction 
with salt and shake out with ether. Evaporate the ether in vacuo, take 
up residue in 4 to 5 drops of alcohol, add 1 to 2 drops alcoholic ferric 
chloride — a green color indicates buchu. 

Confirmatory test can be made by testing a similar residue obtained 
as above with ammoniacal silver nitrate which should be reduced. 

Juniper Communis 

Extract of juniper berries and the oil of that fruit, are conveniently 
considered at this point in connection with buchu. The distilled oil and 
extract of Juniper communis (Pinacese) and probably of J. sibirica are 
chiefly used as adjuvants to more powerful diuretics in dropsical com- 
plaints, and to round out the formulas of pills and tablets designed to 
correct a deranged condition of the kidneys and genito-urinary tract. 

The combinations of juniper and buchu will be found under the dis- 
cussion of the latter drug, and as a general thing either juniper or buchu 
and often both together will be found in any proprietary remedy adver- 
tised as a remedy for diseases of the kidneys. Juniper is one of the com- 
ponents of elixirs of the " Swamp Root " type, where it is combined with 
emodin-bearing drugs, aromatic balsams, methyl salicylate, oil of card- 
amom, and cubeb. 

Juniper oil has a characteristic odor and has been found to contain 
pinene and cadinene. Its specific gravity lies between .865 to .882, and 
it is usually laevogyrate up to -11°. It is miscible with all the organic 
solvents except diluted alcohol. 



CHAPTER XX 
SYNTHETIC ORGANIC NITROGEN COMPOUNDS 

AMINES, DIAMINES AND AMIDES 

The nitrogen compounds in organic chemistry include numberless 
individuals. We have already considered a large class of them under the 
alkaloids, and the following discussion is concerned with those nitro- 
genous medicinal agents which are prepared synthetically. 

ALIPHATIC NITROGENOUS COMPOUNDS 

The simplest representatives of this group may be considered as sub- 
stituted products of ammonia in which one or more of the hydrogens is 
replaced by an alkyl radicle. These bodies are called amines, and are 
primary, secondary, or tertiary, according as one, two, or three atoms 
of hydrogen has been displaced. The lower members are gases or low- 
boiling liquids and are strong bases, usually stronger than ammonia, 
fuming with nitric acid, combustible (thereby differing from ammonia), 
and forming double compounds with gold and platinum chlorides. The 
primary amines give the carbylamine reaction; and are converted by 
nitrous acid into primary alcohols with evolution of nitrogen. The 
secondary amines do not give the carbylamine reaction, and on treatment 
with nitrous acid yield a nitrosamine, which is detected by Liebermann's 
reaction. In order to perform this test the nitrosamine is separated and 
treated with concentrated sulphuric acid; a dark-green solution results 
which, after diluting with water, becomes red, and on adding excess of 
alkali assumes a blue or green color. The tertiary amines usually remain 
unchanged in presence of nitrous acid. 

Moureu and Magnonac recommend the use of ethyl magnesium 
bromide for distinguishing the amines. When the reagent is dissolved 
in ether it reacts with primary and secondary amines in ether with the 
liberation of one molecule of C2H6 for each amine group present in the 
molecule. No reaction takes place with tertiary amines. 

The amines occur among the decomposition products of animal and 
vegetable products, and in our work may be of moment only in rare 
instances; for example, in the examination of extracts of cod livers, or 
of oils prepared from animal matter which is in a state of partial decom- 
position. 

790 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 791 

Hydrazine, H2N NH2, is the parent substance of a large number of 
derivatives, some of which are of considerable importance. 

Hydrazine sulphate, NH2 • NH • H2SO4, called diamidogen or diamine 
sulphate, is a white crystalline solid, soluble in water and used as an anti- 
septic and fungicide. 

Phenylhydrazine, C 6 H 5 NHNH 2 

Phenylhydrazine is either a slightly yellow oil or a colorless crystalline 
mass, melting 23°. It boils with evolution of ammonia at 241-242°, and 
distills unchanged at 120° under 12 millimeters pressure. It is sparingly 
soluble in cold water, more readily in hot, and is veiy soluble in alcohol, 
ether, chloroform, and benzol. It is easily oxidized on exposure to air, 
becoming red and finally dark brown. It has strong basic properties 
and forms salts with acids and carbon dioxide. A solution of the hydro- 
chloride reduces salts of silver, mercury, gold, platinum, and Fehling's 
solution in the cold, in the latter case nitrogen is evolved, and cuprous 
oxide precipitated, and anilin and benzol produced. 

When the hydrochloride is treated with a cold solution of potassium 
nitrite, a yellow nitroso comp., C6Hs(NO)NNH2, separates, which on 
treatment with carbolic acid and strong sulphuric acid, yields a brown 
solution changing to green and blue. 

Phenylhydrazine has well-marked antiseptic properties, and has been 
recommended as a substitute for mercuric chloride. 

A solution of a salt of phenylhydrazine on treatment with caustic 
alkali yields a precipitate of the free base which is removable by shaking 
out with ether. 

Phenylhydrazine reacts with aldehydes and ketones to form hydra- 
zones, and when heated with excess of the reagent if the substance contains 
an OH group a second molecule reacts, producing osazones. It also forms 
hydrazides with hydroxy acids of the sugar group which have the general 
formula RCOHNNHC 6 H 5 , 

Phenylhydrazine may be prepared from anilin by diazotizing and 
subsequently reducing the product thus obtained. It is interesting to 
note that under a strained interpretation of the term derivative, the well- 
known antipyrin could be considered a derivative of acetanilid because 
antipyrin can be prepared from phenylhydrazine, and anilin is one of 
the products of hydrolysis of acetanilid. 

ANTITHERMIN 
CH 3 C(N • NHC 6 H 5 )CH 2 • CH 2 • COOH 

is the hydrazone of acetopropionic acid, which is CH3COCH2CH2COOH. 
It forms colorless, odorless crystals from alcohol, melting 108°, nearly 
insoluble in water, but soluble in alcohol, ether, and dilute acid. It is 



792 ORGANIC SUBSTANCES 

decomposed by alkalies with liberation of phenylhydrazine. It is used 
as an antiseptic and also in phthisis and Blight's disease. 

Hydracetin is the acetyl derivative of phenylhydrazine, CeHsHNNH 
(C2H3O), and is a colorless, crystalline powder, melting 128°, soluble in 
alcohol and hot water, and slightly in ether. 

It is used as an antipyretic in rheumatic fevers, and externally in 
psoriasis and skin diseases. 

Antipyrin — 1 phenyl 2 — 3-dimethyl pyrazolone 

/CO CH /C=CH 

C 6 H 5 N< / or C 6 H 5 N< >0 I 

\N— C-CH 3 X N^==C 

I I I 

CH 3 CH3 CH3 

Antipyrin, known also as phenazone, analgesine, metozine, parodyne, 
phenylone, anodynine, antipyreticum, pyrazoline, sedatine, etc., has an 
extensive use in medicine as an antiseptic and analgesic, and to some 
extent as a hemostatic. It is used either by itself or in admixture for 
bilious and nervous headache, whooping-cough, puerpural fever, sea- 
sickness, gout, sciatica and neuralgic conditions. As a styptic it is used 
principally for hemorrhoids. It will often be found in tablets or elixirs 
mixed with caffein and the bromides, and occasionally acetanilid, acet- 
phenetidin or codein will be included. 

When phenylhydrazine reacts with ethyl aceto-acetate there ulti- 
mately is formed 1-3 phenylmethyl pyrazolone. 

CH 3 COCH 2 COOC 2 H 5 +C6H 5 HNNH 2 = CH 3 C(NNHC 6 H5)CH 2 COOC 2 H5+H 2 

CH3C(NNHC6H5)CH 2 COOC2H5+heat 

.CO— CH 2 
= C 6 H 5 N< I +C2H3OH 

X N=C— CH 3 

On methylating the new substance with methyl iodide antipyrin results. 

The first formula given above has been ascribed to Knorr and the 
second to Michaelis. 

Antipyrin crystallizes in small, lustrous, rhombic needles or plates, 
odorless, and with a somewhat bitter taste, melting 113-114° unless it 
contains hygroscopic moisture, which reduces the melting-point to 105- 
107°, and which may be driven off at 100°. It sublimes when exposed 
to a temperature of 100°. It is very soluble in water, alcohol, and chloro- 
form, very moderately soluble in ether, and but slightly in petroleum 
ether. It is removed from both acid and alkaline solutions by immiscible 
solvents, chloroform being the most efficacious and usually preferred in 
analytical work. Its aqueous solution is alkaline to methyl orange, but 
not to either litmus or phenolphthalein. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 793 

Antipyrin precipitates with a number of the alkaloidal reagents, 
including potassium mercuric iodide, iodin, picric acid, bromin water 
mercuric nitrate, potassium bismuth and potassium cadmium iodides, 
sodium phosphomolybdate, silicotungstic acid, and tannic acid. 

Antipyrin dissolves in nitric acid with a yellowish color and on evapor- 
ating on the steam-bath a purple color develops. If the reaction is checked 
and water added, a violet precipitate is thrown down and the liquid is 
reddish purple in color. The purple coloration which results on evapo- 
rating with nitric acid will mask any test for atropin or strychnin which 
is subsequently made with alcohol potash. 

When nitrous acid is added to a solution of antipyrin a green color 
is produced, and if the antipyrin is in quantity a precipitate of green 
crystals is obtained. The green substance which is visible at consider- 
able dilution is due to isonitrosoantipyrin. On heating the liquid the 
color will change to purplish red. This test is best performed by dis- 
solving a soluble nitrite in a little water, acidifying with sulphuric acid 
and then adding a solution of the suspected substance. It is not character- 
istic of antipyrin being given by other pyrazolones, but it is not given 
by acetanilid or the phenetidines. Pyramidon gives a blue to violet. 

Antipyrin in dilute solution gives a blood-red color with 1 per cent 
ferric chloride solution. It is destroyed by excess of mineral acids. 

It forms certain well-defined salts which are useful in substantiating 
its identification. The picrate, which is very insoluble in water, forms 
yellow crystals, melting 188°, the platinochloride. ferrocyanide and 
salicylate, the latter melting 91-92°. 

Steensma x has described a reaction of antipyrin with p-dimethyl- 
aminobenzaldehyde which is useful for detecting small quantities of the 
substance, especially in toxicological work. The reagent consists of 1 
gram of the above-mentioned substance, 5 mils of 25 per cent hydro- 
chloric acid, and 95 mils absolute alcohol. A trace of the residue suspected 
of containing antipyrin is dissolved in a few mils of the reagent and 
evaporated in a porcelain dish, when a residue with red patches or a red 
ring is obtained. If the amount is extremely minute the reagent should 
be diluted with an equal volume of absolute alcohol. Pyramidon gives 
no color reaction, but salipyrin and acetopyrin react like antipyrin. 

Primot 2 reports a reaction with vanillin which is carried out in the 
same way as the above test. The reagent is prepared by dissolving 1 
gram vanillin in 6 mils dilute hydrochloric acid (1-1) and 94 mils of 95 
per cent alcohol. If antipyrin is present the residue is characterized 
by a deep-orange ring and an orange deposit. Pyramidon does not 
show this color. Cryogenin (metabenzaminocarbazide) gives a yellow- 
green tint under the same conditions. 

1 Apoth. Zeit., 1097, 22, 819. 2 Bull. Soc. Pharmacol., 1909, 370. 



794 



ORGANIC SUBSTANCES 






In the general scheme of analysis antipyrin will appear in consider- 
able quantity in the residue left on evaporating the chloroform extraction 
from an acid solution. Traces of an alkaloid-like substance will have 
been evident in the previous fractions resulting from the petroleum ether, 
and ether extraction, but antipyrin is not removed to any extent by 
either of these solvents. If the residue left on evaporating the chloro- 
form is syrupy in appearance and crystallizes in frostlike forms on cool- 
ing, and if it dissolves readily in water, gives a precipitate with potassium 
mercuric iodide, a green color with nitrous acid, a yellow picrate, melting 
188°, and deep purple on evaporation with nitric acid, the analyst can 
feel satisfied that he has found antipyrin. 

Pyramidon is the only substance in common use which might be 
mistaken for antipyrin. It melts, however, at 108°, gives a bluish- 
violet color with ferric chloride, a blue to violet with nitrous acid, and 
reduces silver nitrate after first yielding a blue color, antipyrin under- 
going no change with silver nitrate. 

From acetphenetidin or acetanilid it is easy to distinguish antipyrin, 
because neither is easily dissolved in cold water, and neither gives a pre- 
cipitate with potassium mercuric iodide, and on hydrolysis with dilute 
acid acetphenetidin yields a solution which on dilution gives a blue color 
with bromide bromate reagent, and acetanilid yields anilin and acetic 
acid, and furthermore gives the carbylamin reaction. 

COMPARATIVE REACTIONS OF ANTIPYRIN, PYRAMIDON AND 

TOLYLPYRIN 





Antipyrin 


Pyramidon 


Tolylpyrin 


Melting-point 


113-114 when anhy- 
drous 


108° 


136-137° 


Ferric chloride 


Red-brown 


Blue by reflected, 
violet by trans- 
mitted light 


Violet 


Silver nitrate 


No change 


Blue silver deposit 


No change 


Nitrous acid 


Bright green 


Blue to violet 


Green 


Nitric acid 


Deep red 


No red 


Cherry red 


Iodin solution 


Brown red precipi- 


Violet coloration ; 


Red-brown precipi- 




tate disappears on 


excess of reagent 


tate which d i s- 




heating 


gives a turbidity 
which dissolves on 
warming 


solves on heating 


Bromin water 


White precipitate 


Concentrated solu- 
tion gives a black 
or gray color 





In making quantitative estimations of antipyrin, the first step con- 
sists in separating it from the body of the product. This may be accom- 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 795 

plished by treating the solution with a slight excess of sodium hydroxide 
and extracting three times with chloroform. If the specimen under 
examination is a pill or tablet in which antipyrin occurs by itself or with 
bromides, an aqueous solution may be rendered alkaline and shaken out 
with chloroform and on filtering, carefully evaporating the solvent in a 
tared dish and drying over sulphuric acid the antipyrin will be pure 
enough to weigh. If it is desired to check the figure by a volumetric 
estimation the following method may be employed : 

To a concentrated aqueous solution of the antipyrin a slight excess 
of iodin solution (100 mils N/20 iodin containing 10 to 20 grams potas- 
sium iodide per liter and 4 mils hydroidic acid sp. gr. 1.7) is added and the 
flask well shaken until the precipitate adheres to the walls and the liquid 
becomes clear. The liquid is then filtered through a small asbestos filter 
and the residual iodin determined in an aliquot by titration with thio- 
sulphate, 21.3 mils N/20 iodin = 0.1 gram antipyrin. 

Lemaire 1 has suggested a volumetric method depending on the pre- 
cipitation of the antipyrin by picric acid and titrating the excess of acid 
with sodium hydroxide. This procedure is of especial value when it is 
desired to estimate antipyrin alone or in the presence of caffein, as the 
latter has no influence. 

ASSAY OF LIQUID HEADACHE MIXTURES 

Method Involving the Precipitation of Antipyrin with Mercuric 
Nitrate and Purification of Caffein. — Measure 25 mils of the sample 
accurately with a standardized pipette or measuring flask, washing out 
the graduate and introducing into a 16 oz. separatory funnel (Squibb 
type). Add a slight excess of 10 per cent sodium hydroxide, shake out 
with four 50-mil portions of chloroform. Each shake-out should consume 
at least five minutes and the separator be allowed to stand for about five 
minutes after each shake-out in order that the solvent may completely 
separate. Run off the chloroform from each extraction into another 
separator, and when the four shake-outs have been united, run into a flask 
of about 300 mih capacity and recover the bulk of the chloroform, which 
can be used over again for subsequent extractions. Finally, run the 
residual chloroform into a tared beaker or dish, wash out the flask with 
a little pure chloroform, evaporate over a steam- or water-bath, using a 
fan or air pressure to hasten the volatilization of the solvent; dry the 
residue for about an hour at a temperature of 100° and weigh. Dissolve 
the residue in the beaker in about 25 mils of water. Pour the mixture 
into a 100-mil graduated flask, wash out the beaker with a little water 
and ad&an excess of mercuric nitrate solution (1 : 3). This is best accom- 

h 1 Pharm. J., 1905, 74, 13. 



796 ORGANIC SUBSTANCES 

plished by adding the reagent in small quantities at a time, allowing the 
precipitate to settle and observing when no further addition of the reagent 
produces a precipitate. Then make up to the mark with distilled water 
and shake thoroughly. When the precipitate has settled, filter off one- 
half of the liquid in a flask, amounting to 50 mils and shake out four times 
with 50-mil portions of chloroform. Unite the chloroform extractions, 
add 10 mils of dilute ammonia water, and shake throughly. Run the 
chloroform into another separator and shake out with water; then run 
the chloroform into a flask, recovering the greater portion as above, and 
then evaporate the remainder in the same flask, over a steam-bath, using 
a current of air to hasten the evaporation. When all the chloroform has 
been driven off, add 15 mils of dilute hydrochloric acid and 15 mils of 
iodin solution (10 mils of iodin — 20 mils of potassium iodide — 100 mils 
water). Allow this to stand overnight, tightly corked. Filter onto a 
dry filter and wash twice with about 10 mils of iodin solution. Then 
transfer the filter containing the precipitate back into the flask in which 
the precipitation was made; add 15 mils of water and about one-third 
of a gram of sodium sulphite and a drop of dilute sulphuric acid. Warm, 
and as soon as the precipitate has dissolved and there is no further color 
of the iodin left, filter into a separator, neutralize with ammonia, and 
shake out five times with chloroform, using the following amounts: 25 
—15— 15— 10— 10 mils. 

Unite the chloroform extractions, insert a pledget of cotton into the 
stem of the separator which has been previously dried with a piece of 
filter paper, run the chloroform through the stem into a tared dish, washing 
out the inside of the separator once with about 5 mils more chloroform, 
evaporate the solvent, and weigh the residue as caffein. This weight 
multiplied by 2 and subtracted from the total weight of the mixture of 
antipyrin and caffein will give the weight of the antipyrin. By multi- 
plying this figure by 1.18, the amount of antipyrin in one fluid ounce 
of the mixture will be obtained, and referring to a comparative table the 
amount in grains may be read off. 

Method Involving the Precipitation of Antipyrin with Picric Acid 
and Titrating the Excess of the Reagent. — Measure out a 25-mil sample 
of the product as described in the previous method, transfer to a separator, 
add an excess of sodium hydroxide, shake out four times with 50-mil 
portions of chloroform, unite all the chloroform extractions obtained, 
wash with about 10 mils of water, and then run the chloroform through 
a pledget of cotton into a flask for recovery. Recover the bulk of the 
solvent and finally evaporate the balance over a steam-bath and leave 
the residue in the flask in which the distillation was made. After the 
solvent has been entirely driven off, add about 10 mils of water and warm. 
Transfer the aqueous liquid to a 50-mil graduated flask, washing out the 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 797 

distilling flask with a little water to make sure that all of the antipyrin 
and caffein is removed, and finally make up to the mark with distilled 
water. Shake thoroughly, remove 10 mils with a pipette, and transfer 
to a small flask. Add from a burette exactly 40 mils of N/20 picric acid ; 
shaking as the addition is made. Allow the solution to stand for about 
an hour, then filter off through a dry filter exactly 25 mils, using a gradu- 
ated flask to obtain the proper quantity. Transfer the aliquot to a flask 
of about 100 mils capacity, washing out the graduate and adding about 
25 mils of water. Add two or three drops of phenolphthalein and titrate 
with an exactly N/10 solution of sodium hydroxide. The end-point is 
reached when one drop of the acid produces a color which does not fade 
and which resembles in shade the color of the solution of acid bichromate 
of potassium. 

A blank must be run on 40 mils of the picric acid solution used. The 
calculation is as follows : 

Multiply the number of mils of N/10 alkali required to titrate the 
excess of picric acid by 4 and subtract this figure from the number of mils 
of N/10 alkali required to neutralize the 40 mils of picric acid. Multiply 
this figure by .009338 and the product by 5. which will give the amount 
of antipyrin in the 25-mil sample taken. 

It is not necessary to have an exact known solution of picric acid, but 
it should be made approximately N/20, as a solution of stronger con- 
centration cannot be obtained, and if a blank is run, its equivalent in 
terms of N/20 picric acid is easily obtained. 

Emery recommends the following methods for determining anti- 
pyrin and the ingredients accompanying it in various combinations. 

Method of Analysis of Headache Mixtures Containing Antipyrin, 
Acetphenetidin, and Codein Sulphate. — Antipyrin may be estimated 
gravimetrically as in the case of caffein, or volumetrically by means of 
a standard alcoholic solution of iodin in the presence of mercuric chloride. 
Its separation from acetphenetidin or acetanilid is easily effected by 
means of chloroform, after subjecting a mixture to hot digestion with 
dilute sulphuric acid, whereby the arlyamids are changed into the cor- 
responding sulphates. 

Ascertain the weight of 20 tablets, then weigh out an amount of the 
finely powdered sample equal to the average weight of one tablet, transfer 
to a separatory funnel, add 50 mils of chloroform, 10 mils of water, and 
a few drops of dilute sulphuric acid. Shake vigorously, allow to clear, 
then draw off through a pledget of cotton and a small dry filter into a 200- 
mil Erlenmeyer. Repeat the extraction four times, distilling off a por- 
tion of the solvent on completion of the third shake-out, in order to accom- 
modate the chloroform from the final two extractions in the same flask. 
On completion of the fifth and final shake-out, distill the chloroform down 



798 ORGANIC SUBSTANCES 

to about 10 mils add 10 mils of dilute sulphuric acid (1 : 10 by volume), 
continue heating gently until all the solvent has passed over, remove to 
steam-bath, and digest till the volume of liquid amounts to about 5 mils, 
add 10 mils of water, and continue the treatment until the liquid is again 
reduced to 5 mils 1 . In order that the hydrolysis may be complete, that 
is, no particles of acetphenetidin remain on the sides of the flask, rotate 
the latter gently from time to time during the process of digestion, or 
better, perhaps, add a few drops of alcohol or chloroform now and then. 

Antipyrin. — Transfer the aqueous acid solution of phenetidin sul- 
phate and unchanged antipyrin to a separatory funnel by the aid of 
water, so that the final volume does not exceed 20 mils. Make seven 
extractions with 30-mil portions of chloroform, clearing and drying the 
solvent by means of a cotton pledget and dry filter as hereinbefore de- 
scribed. Distill the united chloroformic extractions down to about 10 
mils, transfer to a tared 50-mil beaker, evaporate on a steam-bath to 
apparent dryness; cool, and weigh. It has been found that antipyrin 
retains traces of moisture and chloroform with great obstinacy, hence 
several days are required, even with the help of a vacuum desiccator, 
to approximate to a constant weight. It is therefore more expeditious 
to subject the crude residue to volumetric estimation. To this end dis- 
solve the antipyrin in 95 per cent alcohol, transfer to a 100-mil graduated 
flask, and fill to the mark. Titrate an aliquot (20 mils or more if the 
amount of antipyrin is relatively small) of the alcoholic solution of anti- 
pyrin thus prepared with an iodin solution prepared and standardized 
in the following manner: Make up three solutions — A, containing 1.351 
grams of resublimed iodin in 100 mils of 95 per cent alcohol; B, contain- 
ing 1 gram pure antipyrin in 100 mils of 95 per cent alcohol; C, contain- 
ing 5 grams of mercuric chloride in 100 mils of 95 per cent alcohol. Into 
a 100-mil Erlenmeyer measure from a burette 20 mils of Solution B, and 
by means of a pipette 10 mils of Solution C, then run in from a burette 
the iodin solution until a faint yellow coloration persists after a lapse of 
three to five minutes. Run several duplicates and it will be found that, 
under the conditions obtaining in the experiment, approximately 20 mils 
of the iodin solution thus standardized will very nearly correspond to 1 
mil of antipyrin solution, or, by weight, 10 mg. of antipyrin. The 
value of the iodin solution in terms of antipyrin having been thus deter- 
mined, subject the aliquot of the alcoholic solution of antipyrin from 
sample under examination to a similar treatment, basing the final result 
on an average of two or more titrations. 

Since the presence of either acetphenetidin or codein is apparently no 
bar to the accuracy of the above reaction, it is wise to check the value for 
antipyrin already obtained by treating the original sample as follows: 
Weigh out on a small (5.5 cm.) filter an amount of the powdered sample 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 799 

equal to the average weight of one tablet, wash with successive small 
portions of 95 per cent alcohol, in quantity about 20 to 30 mils, sufficient 
at least to remove all the antipyrin in the mixture. Collect solvent in 
a 100-mil Erlenmeyer, add 10 mils of solution C, then run in the standard 
iodin until a faint yellow coloration persists. The number of cubic centi- 
meters of iodin required to effect this should agree approximately with 
the value previously obtained. 

Acetphenetidin. — Wash the filter used to dry the chloroform solution 
of antipyrin once with 5 mils of water, allowing the latter to run into 
the separator containing the phenetidin sulphate. Treat the solution 
with successive small portions of solid sodium bicarbonate until an excess 
of this reagent, after complete neutralization of the sulphuric acid, per- 
sists at bottom of the liquid. Now add 60 mils of chloroform and, for 
every 100 mg. of acetphenetidin known or believed to be present, about 
5 drops acetic anhydride; shake for some time vigorously, allow solvent 
to clear, then pass through cotton, and dry filter into a 200-mil Erlen- 
meyer, exactly as in the extraction of caffein. Distill over 50 mils of the 
chloroform, make up to 60 mils with fresh solvent, and extract again. 
Draw off chloroform, distill as before, this time about 60 mils, then make 
a third and final extraction. Distill to about 10 mils, transfer by pouring 
and rinsing with small quantities of chloroform to a tared 50-mil crys- 
tallizing dish, evaporate on the steam-bath to apparent dryness, finally 
removing any considerable excess of acetic anhydride by repeated addi- 
tions of about 1 mil of fresh chloroform, containing 1 to 2 drops alcohol. 
The acetphenetidin should finally appear as a whitish, crystalline mass, 
having usually a faint acetous odor. This will entirely disappear on 
standing some time in the open, or more quickly in a vacuum desiccator 
over lime. The residue should be repeatedly weighed until it suffers no 
further loss. 

Codein Sulphate. — The estimation of codein can be carried out during 
the hydrolysis of acetphenetidin. Wash the filter used to dry the chloro- 
form solution of antipyrin and acetphenetidin once with 5 mils of water, 
receiving latter in the separator containing the aqueous-acid solution of 
codein. Add solid sodium bicarbonate in slight excess, then extract three 
times with 50 mils of chloroform. Clear, dry, and collect solvent from 
the three operations in a 200-mil Erlenmeyer, then distill down to 10 
mils. Transfer to a 50-mil tared beaker, evaporate to apparent dryness 
on the steam-bath, moisten the amorphous residue with a few drops of 
alcohol, evaporate again, cool, and weigh. This weight, multiplied by 
the factor 1.3144, will give the amount of codein sulphate originally present 
in the sample. It is recommended that this result, which is likely to be 
somewhat high, be verified by titrating the crude codein with N/50 sul- 
phuric acid, using 1 drop of methyl red solution as indicator. 



800 ORGANIC SUBSTANCES 

In the event that acetanilicl instead of acetphenetidin is employed 
in combination with antipyrin and codein sulphate, it would be necessary 
to modify the procedure only as regards the final treatment of the aqueous 
acid solution containing in addition to antipyrin the acetanilid, which 
after being subject to hydrolysis and freed from the former is titrated with 
potassium bromide-bromate. 



ESTIMATION AND SEPARATION OF ANTIPYRIN FROM VARIOUS SYN- 
THETIC PRODUCTS BY MEANS OF ITS PERIODIDE. 1 

Direct estimation when no other substance is present which will itself 
or after treatment with iodin be extracted by chloroform. 

Method I. — Aqueous solution of the antipyrin (containing not over 
.25 gram antipyrin in 10 mils water) is poured into a large separatory 
funnel, 20 mils saturated sodiun bicarbonate solution is added, a few mils 
of washed chloroform (to remove alcohol), 100 mils water and about 50 
mils of approximate N/10 iodin is added. The solution is shaken 
thoroughly about six times at intervals. The excess of iodin is removed 
by adding a few mils of sodium thiosulphate and shaking. The resulting 
iodoantipyrin is shaken out with three 30-mil portions of chloroform 
and washing each extract with about 10 mils water in a small separa- 
tory funnel and filtering through cotton into a tared 150-mil Erlenmeyer 
to a condenser, and chloroform distilled down to recover most of the the 
chloroform, until about 10 mils remain. This is then evaporated to dry- 
ness on the water-bath (preferably over a blast) and dried in oven at 
110° C. for half hour. 

Multiply the iodoantipyrin by factor .5992 (H = l) to antipyrin. 



DETERMINATION OF ANTIPYRIN. SEPARATION BY PERIODIDE METHOD 
FROM ACETANILID, SULPHONAL, AND PHENACETIN 

Method II. — To an aqueous solution of antipyrin (not over .25 gram 
in about 50 mils water) in a 500-mil Erlenmeyer flask, add 20 mils strong 
hydrochloric acid, about 100 mils of approximate N/10 Iodin in potas- 
sium iodide, shake well and allow tarry precipitate to settle clear (should be 
allowed to stand at least three hours). Ten mils hydrochloric acid is 
sufficient if allowed to stand overnight. Pour off the clear supernatant 
liquid through a funnel plugged and overlaid with glass wool and a little 
asbestos. Wash the tar by decantation about eight or nine times with 
about 20 mils acid water (5 per cent HC1 solution) each time keeping as 
much of the tar in the flask as possible. Then place the funnel contain- 
ing some of the tarry precipitate in a large separatory funnel, dissolve 
1 W. O. Emery and S. Palkin. J. Ind. & Eng. Chem., 1914, 6, 751. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 801 

the tar in the Erlenmeyer by warming slightly with about 50 mils of 
methyl alcohol (free from ethyl alcohol and acetone) making sure that 
all the tar is in solution, pour through funnel into the separatory funnel, 
thus dissolving the tar left on the glass wool. Wash Erlenmeyer and 
funnel several times with methyl alcohol from a wash bottle until every- 
thing (all the tar) has been washed in the separatory funnel. Add 30 mils 
saturated sodium bicarbonate solution, dilute with about 50 mils water, 
shake thoroughly three to four times at intervals, allowing to stand a 
few minutes each time. Remove the excess of iodin with a few mils 
of strong sodium thiosulphate solution, now shake out the resulting iodo- 
antipyrin with 40 mils chloroform, draw off the chloroform extract into 
a small separatory funnel and wash with about 10 mils water, and filter 
through cotton into a tared 150-mil Erlenmeyer. Repeat this operation 
twice with 40 mils chloroform each time, using the same wash water, 
(three times in all). Distill the chloroform extracts to recover most of 
chloroform as described in method I, and finally evaporated to dryness 
on steam-bath, dry in oven at 110° for half -hour and weigh the iodoanti- 
pyrin. 

Multiply the iodoantipyrin by the factor .5992 (H = l) to obtain 
tne amount of antipyrin. 



ASSAY OF TABLETS CONTAINING CAFFEIN AND ANTIPYRIN IN 

ADMIXTURE 

Method. — Weigh out on a metal scoop or watch-glass 0.25 gram of 
the sample, transfer to a 150-mil separatory funnel with 5 mils alcohol- 
free chloroform and 10 mils water, add 0.5 gram sodium bicarbonate and 
about 10 mils N/5 iodin (or double the quantity of N/10 iodin), then 
shake vigorously one minute, after which operation a slight excess of 
iodin should still be apparent in the liquid menstruum, provided all the 
antipyrin has been converted to iodoantipyrin. If, however, all the 
iodin has been thus expended, a little more should be added and the mix- 
ture again shaken. Now discharge the uncombined iodin by means of 
a small crystal of sodium thio sulphate, add 20 mils U. S. P. chloroform 
and shake. After clearing, draw off solvent into a second separator 
containing 5 mils water, shake, and after clearing pass the chloroform 
through a small dry filter into a tared 50-mil beaker, evaporate to apparent 
dryness on the steam-bath, accelerating this operation by means of an 
air blast, if available. Repeat extraction with two (three, in case N/10 
iodin were used) 25-mil portions of chloroform, washing, filtering, and 
evaporating each portion in rotation substantially as directed for the 
first portion. Recover all traces of crystalline products separating about 
tips of funnels and edge of filter by judicious washing with chloroform. 



802 ORGANIC SUBSTANCES 

The final colorless, crystalline residue of caffein and iodoantipyrin is 
dried one-half hour at 100°, then cool, and weigh. Designate this 
weight A. 

Dissolve this residue in 5 mils glacial acetic acid, add 10 mils saturated 
aqueous solution sulphur dioxide, then transfer the resultant liquid by 
pouring and rinsing with hot water to a 400-500 mil beaker, until the final 
volume amounts to about 200 mils. Add aqueous silver nitrate solu- 
tion (containing about 0.25 gram silver nitrate) and follow with a few 
drops of nitric acid, then heat nearly to boiling, stirring the while in order 
to agglomerate the silver iodide. Add about 15 mils cone, nitric acid, 
cover beaker with watch-glass and boil gently five minutes. Filter by 
decantation through a tared Gooch, wash precipitate twice with boiling 
water, finally transferring the silver iodide completely to the Gooch, 
washing several times with hot water and finally with alcohol. Dry 
one-half hour in air bath at 110°, cool, and weigh. 

The weight of silver iodide multiplied by the factor 0.8012 yields the 
quantity of antipyrin present in sample taken. The quantity of caffein 
present in sample is ascertained by subtracting the product, obtained by 
multiplying the weight of silver iodide by the factor 1.3374, from the weight 
designated A. 



ASSAY OF LIQUID HEADACHE MIXTURE CONTAINING ANTIPYRIN AND 

CAFFEIN 

Method. — By means of a pipette standardized at 20°, transfer 10 mils 
of the solution, previously warmed or adjusted to 25°, to a 150-mil sepa- 
rator^ funnel containing 0.5 gram sodium bicarbonate. Add about 15 
mils N/5 iodin (or double the quantity of N/10 iodin), then shake vigor- 
ously one minute. All succeeding operations are identical with those 
outlined for the powder mixture. 

Comments and Suggestions. — The foregoing procedure is based on 
the fact that, when an aqueous solution of iodin and sodium bicarbonate 
is permitted to react with antipyrin, whether alone or with other sub- 
stances as caffein, mono -iodoantipyrin is formed. This latter substance, 
together with caffein, is thereupon extracted with chloroform, the weight 
of such mixture ascertained and the iodin therein estimated as silver 
iodide, from which the antipyrin is calculated by means of the appro- 
priate factor. In view of the somewhat radical treatment with dilute 
nitric acid, to which the caffein is necessarily subjected incidental to the 
precipitation of silver iodide, a direct determination of that substance 
is impracticable. The quantity of caffein is, however, ascertained by 
subtracting the amount of iodoantipyrin, as calculated from the silver 
iodide, from the combined weight of caffein and iodoantipyrin. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 803 

The use of alcohol-free chloroform is specified in order to preclude the 
possible formation of iodoform, the presence of which would necessarily 
render the method valueless. 

The final washing of the silver iodide with alcohol should be thorough 
in order to eliminate certain unidentified organic substances arising from 
the action of nitric acid on the antipyrin complex. 

There are several antipyrin compounds used medicinally. 

Antipyrin Salicylate, CnH^NaOCeB^OHCOOH 

is a weak chemical combination of antipyrin and salicylic acid. 

It occurs as a white, coarsely crystalline powder, or in hexagonal 
tabular crystals, melting at 71 to 92° C, odorless, slightly sweet, soluble 
in alcohol, less readily in ether. It is decomposed by acids with the 
elimination of salicylic acid, and by alkalies with the elimination of anti- 
pyrin. 

Its aqueous solution is rendered milky by tannic acid, then colored 
green by the addition of a few drops of fuming nitric acid. It is colored 
deep red by ferric chloride, passing to violet red on copious dilution with 
water. 

Tussol— Antipyrin Mandelate, CnHi 2 N 2 • C 6 H 6 • CHOH • CO OH, 

a salt of mandelic acid, CeHoCHOH • COOH, and antipyrin. It is a 
white crystalline powder, having a bitter taste and melting at 52 to 53° C. 
It is soluble in 15 parts of water, 3 to 4 parts of alcohol, or 25 to 26 parts 
of ether, producing solutions of acid reaction. When heated above the 
melting-point, it gives off the odor of bitter almonds, and finally burns 
without leaving a residue. It is split into its constituents by milk and 
by alkalies. 

Its aqueous solutions give the reactions for antipyrin ; if warmed with 
potassium permanganate it develops the odor of benzaldehyde, but is 
not effected by silver nitrate, barium nitrate, dilute sulphuric acid, or 
hydrogen sulphide; useful in the treatment of whooping-cough. 

FERROPYRIN, (C u H 12 N 2 0) 3 (FeCl 3 ) 2 

Ferropyrin is a compound of antipyrin and ferric chloride, containing 
about 35 per cent of ferric chloride and 64 per cent of antipyrin. 

It is a yellowish red, crystalline powder, having an acid-astringent 
taste. It is soluble in 5 parts of cold water, but requires 9 parts of hot 
water for solution; it is soluble in alcohol, but insoluble in ether. 

It should form a clear blood-red solution in water. Its aqueous solu- 
tion 1 : 5 yields a precipitate of ferric hydroxide on addition of ammonia 



804 ORGANIC SUBSTANCES 

in excess, and the nitrate should give no reaction for nitric or sulphuric 
acid, nor heavy metals, and should yield a residue on evaporation, which 
is completely volatilized when heated on platinum. After acidification 
with nitric acid, the filtrate yields a white precipitate with silver nitrate 
and in the filtrate from this the antipyrin may be detected by means 
of ferric chloride or by nitrous acid. 

It is hematinic, hemostatic, astringent, analgesic, and tonic. 

Antipyrin Iodide — Iodopyrin 

The compounds of iodin and antipyrin have been studied by Emery 
as noted under the methods for the quantitative determination of the 
base. One of these which is claimed to contain but one atom of iodin 
is used to a limited extent as an antipyretic, alterative, and analgesic in 
tuberculosis, syphilis, typhoid fever, bronchitis, and asthma. 

Antipyrin Monobromide 

A compound analogous to the one previously mentioned, but contain- 
ing bromin instead of iodin, is called bromopyrin, and is used as an 
antipyretic and antiseptic. It melts 114° C. The name a Bromopyrin " 
is applied to mixtures of the general type of caffein, antipyrin, and alkali 
bromides. 

Methylenediantipyrin — Fermopyrin 

This product results from heating together antipyrin and formal- 
dehyde. 

Methylenediantipyrin tetrabromid, salubrol, has been described under 
formaldehyde. Salubrol is an orange-yellow powder, melting 155° and 
used as a substitute for iodoform. 

Antipyrin Salicylacetate 

There seem to be two products bearing this name, one of which is a 
salt of acetylsalicylic acid and the other a somewhat uncertain mixture. 
They combine the virtues of antipyrin and salicylic acid, and are hence 
used in rheumatic condition where an analgesic is required. 

The salt of acetylsalicylic acid is also called acetopyrin and acopyrin, 
and the other product pyrosal. 

Antipyrin Resorcylate — Resalgin 

Resalgin or resorcylalgin purports to be a salt of betaresorcylic acid 
and forms colorless needles melting 115° C. It is used as an antiseptic. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 805 

Resopyrin 

Resopyrin differs from resalgin in that it is a product resulting from 
the fusion of molecular proportions of resorcin and the base. It is another 
of those compounds where chemical individuality is a matter of doubt. 

Chloral hydrate and antipyrin combined are called Hypnal, and the 
crystalline product melts at 67° and is used in cases of insomnia and spas- 
modic cough. It reduces Fehling's solution, gives a blood-red color with 
ferric chloride and chloroform on boiling with alcoholic potash. 

Antipyrin and paramidobenzenesulphonate produce sulphopyrin, 
and a mixture of carbolic acid and the base is called Phenopyrin. 

It will be noted from a survey of the above products that while there 
are a few well-defined salts of antipyrin, the majority of the compounds 
are of a more or less doubtful nature. Antipyrin is not a strong base 
chemically and hence a hard and fast union with the weak acids and phenols 
is not to be expected. While it is not questioned that an equmbrium of 
greater or less stability may be obtained as the result of a fusion, the 
ease with which the compounds are separated and identified when sub- 
jected to the simple action of water is sufficient to show that no very 
permanent compound has been formed. 

Paratolyldimethylpyrazole 

Tolylantipyrin is prepared by treating paratolylhydrazine with aceto- 
acetic ester and methylating the resulting product. 

.CO— CH 

CH3C 6 H4N< || 

X -N— C— CH 3 

I 
CH3 

It is a colorless crystalline substance with a bitter taste and melts 
/JJ&-137 . It resembles antipyrin in its physiological properties, and 
might at first be mistaken for it, but the difference in its chemical character- 
istic will be noted in the table of comparative reactions on page 794. 

The salicylate of this base is called Tolysal. It is analogous to anti- 
pyrin salicylate, and is used as an antineuralgic and antirheumatic. 

Thioantipyrin 
CH 3 

I 
C=N — CH3 

S<^)N— C 6 H 5 

HC=C 

Melts 166°. It gives a transient green color with ferric chloride, 
but not with nitrous acid. 



806 ORGANIC SUBSTANCES 

Selenopyrin melts 168°. It gives no color with ferric chloride and 
only a faint green with nitrous acid. 

Melubrin 

Melubrin is sodium l-phenyl-2, 3-dimethyl-5-pyrazolon-4-amido- 
methan-sulphonate, 

,CO C • NH ■ CH 2 • S0 3 Na 

^NCCHa)— CCCHs) 



c 6 h 5 n/ 



the sodium salt of l-phenyl-2, 3-dimethyl-5-pyrazolon-4-amido-methan- 
sulphonic acid, differing from antipyrin in that a sodium-amido-methan- 
sulphonate group, • NH • CEbSOsNa, has replaced a hydrogen atom of 
the pyrazolon group. 

It is a white, odorless, almost tasteless crystalline powder, readily 
soluble in water, but slightly soluble in alcohol. The aqueous solution 
is neutral in reaction but unstable. 

If about 0.2 gram of melubrin dissolved in 5 mils of water is boiled 
with 3 mils of diluted hydrochloric acid, sulphur dioxide and formaldehyde 
will be liberated. 

If one-half of the solution thus formed is treated with 3 drops of 
sodium nitrite solution and 5 mils of an alkaline solution of betanaphthol, 
a red precipitate will be produced. 

If the remainder of the above solution is treated with 1 gram of sodium 
acetate and 15 mils of a saturated aqueous benzaldehyde solution, a 
yellowish-white, flocculent precipitate will be formed which, when washed 
and dried, will melt at 173°. 

If 0.4 to 0.5 gram of melubrin is weighed into a platinum dish, treated 
with dilute sulphuric acid, and heated to constant weight, the sodium 
sulphate thus formed should weigh 0.2160 to 0.2250 gram for each gram 
of material used, representing a sodium content of 6.99 to 7.28 per cent. 
It is used as a antipyretic in fever and is analgesic, 

Iodomethyl Phenylpyrazolon 

A substance claiming to be an iodin derivative of this character is 
sold under the name of Mydrol. It is soluble in water and alcohol and 
is used as a mydriatic. 

Pyramidon 

' The use of pyramidon in medicine is probably on the increase, and the 
analyst may encounter it in any new mixture intended for antipyretic 
purposes. Especial note is made of this because a worker experienced 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 807 

in the analysis of medicines knows that there are practically only three 
antipyretics in general use and that the extent of their prevalence is in 
the following order, acetanilid, acetphenetidin, and antipyrin. 
Pyramidon is phenyl-dimethyl-dimethylamino-pyrazolon, 



C 6 H5N<^ 



CO C-N(CH3) 2 

II 
N(CH3)-C(CH 3 ) 



differing from antipyrin in that a dimethylamino group, N(CHs)2, has 
replaced a hydrogen atom of the pyrazolon nucleus. 

It is prepared by the reduction of nitroso-antipyrin to amidoanti- 
pyrin and treating this with methyl chloride or iodide. 

It forms small, colorless, slightly alkaline crystals, melting at 108° 
C; almost tasteless; soluble in 11 parts of cold water and readily soluble 
in alcohol, ether, and benzene. Its aqueous solution saturated at 70° C. 
deposits oily globules of pyramidon on boiling. 

Ferric chloride colors the neutral or slightly acidulated solution of 
pyramidon a bluish-violet color; nitrous or nitric acid produces a fugitive 
blue-violet color; silver nitrate produces an intense violet coloration when 
added to the aqueous solution, followed by the formation of a black pre- 
cipitate of metallic silver, and the same color is produced by platinum 
chloride, by ammonium persulphate, and by lead dioxide. In hydro- 
chloric acid solution pyramidon gives a fine crystalline double salt with 
mercuric chloride. 

Pyramidon may be estimated by means of picric acid by the same 
process as antipyrin. 

Pyramidon Acid Camphorate, C13H17N3O • CioH 16 04 

is an acid salt of pyramidon and camphoric acid. It is a white, crystal- 
line powder of acid reaction, melting (indefinitely) at 84 to 94° C, soluble 
in 20 parts of water or 4 parts of alcohol. 

It gives the characteristic reaction of pyramidon with silver nitrate. 
If the solution in hot water is made alkaline with caustic soda, the pyrami- 
don may be shaken out with chloroform; if the residual aqueous liquid 
is then acidified with sulphuric acid the camphoric acid (melting-point 
186° C.) may be shaken out with ether. 



Pyramidon Neutral Camphorate, (CiaHtfN-sO^-CioHieO* 

is a neutral salt of pyramidon and camphoric acid. It is a white, crystal- 
line powder, melting (indefinitely) at 80 to 90° C. It dissolves with acid 
reaction in 15 parts of water or 2 parts of alcohol. 



808 ORGANIC SUBSTANCES 



Pyramidon Salicylate, C13H17N3O • CyHeOa 

is a salt of pyramidon and salicylic acid. It is a white, crystalline powder, 
having an acid reaction and melting indefinitely at 68 to 70° C. It is 
soluble in 16 parts of water or 5 to 6 parts of alcohol. 

The aqueous solution is colored intensely red by ferric chloride, and 
produces a white precipitate with silver nitrate, the solution assuming 
a violet color after a short time. 



Trigemin 

Trigemin is prepared by combining butylchloralhydrate and pyrami- 
don, and is used as an analgesic and sedative. It is soluble in water and 
other ordinary organic solvents except petroleum ether, which has but 
slight action, and melts 83-85°. 

Arhovin, Ci Hi 3 • C 6 H4(COOC 2 H 5 ) (C 6 H 5 ) 2 NH 

Arhovin is an addition product of diphenylamine and thymylbenzoic 
acid. It is an oily liquid, with an aromatic odor and a cooling and after- 
ward burning taste. It is insoluble in water, but dissolves in alcohol, 
ether, chloroform, and oily liquids and is employed as an antiseptic in 
venereal troubles. 



* Agathin— Salicylalphamethyl Phenylhydrazone, C 6 H5-N(CH 3 )N : CH CeHiOH 

Agathin is a reaction product of alphamethyl phenylhydrazine and 
salicylic aldehyde. It forms yellowish crystals melting 74° C, soluble 
in alcohol, ether, and benzol, but insoluble in water. It is used as an 
antirheumatic and antineuralgic. 



DIAMINES 

The diamines are derived from a double molecule of ammonia by the 
replacement of two or more of the hydrogen atoms by hydrocarbons of 
the olefine, phenylene, or naphthalene series. 

Ethylene-diamine, NH 2 CH 2 • CH 2 NH 2 

Ethylene-diamine is formed by the reaction of ethylene chloride or 
bromide and alcoholic ammonia at 100-120° C. It is a viscous volatile 
liquid, with a slight ammoniacal odor, sp. gr. .902 at 15° C, boiling 117°, 
easily soluble in water but insoluble in ether. It dissolves albumen and 
fibin, and is employed in medicine as an adjuvant to the treatment of 
diphtheria. 






SYNTHETIC ORGANIC NITROGEN COMPOUNDS 809 

It forms with mercuric sulphate a white crystalline substance known 
as sublamine, which is soluble in water and glycerin and is used instead 
of mercuric chloride in syphilis, gynecological practice, and as a vaginal 
douche. 

A solution of silver phosphate in an aqueous solution of ethylene- 
diamine is called Argentamine, and is used as an antiseptic or astringent 
in gynecological and ophthalmic practice. 

An aqueous solution containing 25 per cent ethylene diamine and 25 
per cent cresol is used as a bactericide. Kresamine is a product of this 
type. 

Diethylene-diamine — Piperazine, C4H10N2 

Piperazine is a well-defined base having the composition 

H 

I 

N 

HsC./NcHa 

H 2 cl J-CH 2 

N 

I 
H 

It forms colorless, lustrous, tabular crystals, hygroscopic, which melt 
at 44° C. (104-107° when anhydrous and boils at 145°). It is extremely 
soluble in water, forming strongly alkaline but non-caustic solutions, 
which dissolve carbon dioxide. It is not so readily soluble in alcohol. 
It is volatile. It forms soluble salts with acids, and with uric acid it forms 
a very soluble salt (in 50 parts of water; lithium urate requires 368 parts 
of water) . It is not affected by chromic acid, but is slowly oxidized by 
potassium permanganate. 

In aqueous solution it gives a characteristic scarlet-red precipitate" 
with potassium-bismuth iodide, a white precipitate with Nessler's reagent, 
and is precipitated light blue by copper sulphate, white by mercuric 
chloride, lemon yellow (crystalline) by picric acid and grayish by tannic 
acid. 

Piperazine forms a series of rrydrates containing from one to six mole- 
cules of water, the latter being the most readily obtained. 

The picrate is very insoluble in water and is obtained by simply add- 
ing an excess of a solution of the reagent. The reaction may be used as 
a means of estimating piperazine, and the details are the same as for 
determination of antipyrin by the same reagent. 



810 ORGANIC SUBSTANCES 

When sodium nitrite is added to a solution of piperazine in dilute 
hydrochloric acid, and the mixture warmed, a dinitrosopiperazine sepa- 
rates which, on recrystallization from boiling water, forms yellowish plates 
melting 158°. It gives a deep blue color after some minutes with a solu- 
tion of phenol in sulphuric acid. 

Piperazine is used in gout, for the relief of irritation of the bladder, 
rheumatism, renal colic, and for the prevention of the formation of renal 
and vesical calculi. 

Sidonal — Piperazine Quinate 

•CH2CH 2 \ 
NH< >NH • 2C 6 H 7 (OH) 4 (COOH) 



^CH 2 CH 2 ' 

the normal salt of piperazine and quinic acid. 

It forms a white, crystalline powder, melting at 168 to 171° C, and 
having a faint acid taste and reaction. It is very soluble in water and 
forms salts on mixing the aqueous solutions with solution of alkali car- 
bonates and evaporating to dryness. 

It responds to tests for piperazine (precipitate with potassium-bismuth 
iodide, etc.) and quinic acid. 

Sidonal is used as a uric acid solvent in gout, neurasthenia, etc. 

Dimethyl Piperazine— Lupetazin, NH^Hs-CHs^NH 

Lupetazin is a colorless oily liquid boiling 153-158°, the base of lycetol. 
It gives precipitates with iodin, picric acid, and bromin water, but not 
with Mayer's reagent. 

Lycetol — Dimethyl Piperazine Tartrate 

<CH(CHs) • CH 2 \ 
>NH+H 2 C4H406 
CH 2 CH(CH 3 ) ' 

It is a white, odorless powder, melting at 250° C, anhydrous, but 
slightly hygroscopic. It is soluble in water, forming agreeably acidulous 
solutions. 

Ethylene-ethenyl-diamine — Lysidine 

Lysidine is an hygroscopic, reddish-white crystalline substance with 
a peculiar odor resembling coniin and having the composition 

CH 2 NH X 
I >C-CH 3 . 

CH 2 — N^ 

It dissolves easily in water and is used for the same purposes as piperazine. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 811 

It melts 100-106°, very soluble in alcohol, somewhat in chloroform, but 
insoluble in ether. It gives precipitates with the general reagents for 
alkaloids, and forms a soluble urate. 

Naphthylamines, Ci H 7 NH 2 
Naphthylamine occurs in two forms, the alpha and beta. 



i i i 

U\> TH2 x/V 

NH 2 

The alpha melts 30°, boils 300° C, soluble in alcohol and ether. The 
beta melts 112°, boils 294° C, soluble in alcohol, ether, slightly in water. 

Thermin — Tetrahydrobetanaphthylamine Hydrochloride, CioH n NH 2 • HC1 

Thermin forms colorless to reddish-white crystals, melting 237° C, 
soluble in water and alcohol. It is used as a mydriatic, and to increase 
the bodily temperature. 

Pyridin 

The nitrogenous bodies with the nitrogen atom in a closed complex 
are usually derivatives of pyridin, quinolin, or acridin. The plant 
alkaloids are generally derivatives of the first two. 

Pyridin, C5H5N, occurs in bone oil or coal tar. When pure it is a 
colorless,- mobile liquid with a pungent characteristic odor, boiling 115° 
and miscible with water in all proportions. It is a strong base, turning 
red litmus blue and combining with acids to form crystalline salts. The 
platinochloride crystallizes in orange-yellow needles readily soluble in 
water, but on boiling, a very sparingly soluble j r ellow salt separates. If 
pyridin or its homologues are treated with methyl iodide, a methiodide 
is produced, and if this is then subjected to the action of heat in presence 
of potassium hydroxide a very pungent and disagreeable odor is evolved. 
It does not give the carbylamine reaction nor does it react with nitrous 
acid. 

Pyridin has the structure 

H 
C 

Hc/N^H 

Hcl ,CH 

N 



812 ORGANIC SUBSTANCES 

It is unsaturated, but the positions of unsaturation are not as yet satis- 
factorily established. 

Piperidin obtained by boiling piperin with alkalies,' is hexahydro- 
pyridin 



H 2 
C 



H 2 (X ^CHa 

H 2 Cv /Cr±2 

N 
a colorless liquid boiling 106° with a penetrating odor like pepper. 

Pyrrole 
CH=CH 

NH 
CH=CH 

Pyrrole and two isomeric methyl pyrroles, are associates of the pyridin 
bases in coal tar and bone oil. Pyrrole is a colorless pungent-tasting 
liquid with a chloroform-like odor, sp. gr. .9669 at 20°, boiling 130-131°. 
It is a weak base, dissolving in acids, and is indifferent to .alkalies. It 
is soluble in alcohol and ether, but almost insoluble in water. It forms 
an unstable red picrate, melting 71°, and a grayish-brown tetraiodo com- 
pound melting between 140-150°. 

Pyrrole turns brown on exposure to the air. Heating with acid gives 
pyrrole red, and its vapor reddens a piece of pine wood moistened with 
hydrochloric acid. A solution of alloxan on boiling with a small quantity 
of pyrrole turns blue, changing to red on cooling, and to green and blue 
on addition of alkali. 

If pyrrole is added to a weak solution of isatin in water, acidulated 
with sulphuric acid and cooled to 5°, an indigo blue substance is obtained, 
which is soluble in concentrated sulphuric acid to a blue to bluish-black 
solution. 

A solution of phenanthraquinone in acetic acid on treatment with 
pyrrole and acetic acid yields a brown precipitate soluble in chloroform 
with a violet-red color. An aqueous solution of benzoquinone when 
treated with pyrrole and dilute sulphuric acid yields a dark-green pre- 
cipitate. 

Iodol— Tetraiodo Pyrrole, C4I4NH 

Iodol is a grayish-brown powder prepared by the action of iodin in 
potassium iodide on a solution of pyrrole in the presence of alkali. It 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 813 

has a faint odor, and on heating is decomposed without melting between 
140-150°. It is only slightly soluble in water, but dissolves in the ordinary 
organic solvents and in acids. It is turned black by hydrochloric acid, 
and forms an addition compound with eucalyptol, melting with decompo- 
sition at 112°. With sulphuric acid it gives a green color changing to 
violet, and on warming an alcoholic solution with nitric acid a bright- 
red color appears. 

Iodol is valuable chiefly as an antiseptic and alterative, and is used 
in syphilis, scrofula, etc., as a substitute for potassium iodide. Locally 
it is employed as a spray for throat affections, and as an ointment or 
powder or with collodion in chancre, chronic ulcers, and other suppur- 
ative conditions. 

A compound of iodol and egg albumen is recommended for internal 
administration. It is a yellow, tasteless, and odorless powder, soluble 
only in dilute alkalies. 

Quinolin and its Derivatives 

Quinolin, C9H7N, and its isomer, isoquinolin, occur in bone oil 
and coal tar, but for commercial purposes quinolin is prepared syn- 
thetically by Skraup's reaction. Anilin and glycerol are heated with 
a dehydrating agent such as sulphuric acid and an oxidizing agent such 
as nitrobenzol. In the reaction it is probable that acrolein is first formed, 
which then condenses with anilin, forming acrylanilin, and the latter 
under the oxidizing action of nitrobenzol loses two atoms of hydrogen 
and is converted to quinolin. 

H H • 

HC C CH 

I I I +H 2 

HC C CH 

\ C /\ N / 
H 

Derivatives of quinolin may be obtained by Skraup's reaction, using 
derivatives or homologues of anilin. 

Quinolin is a colorless highly refractive oil, sp. gr. 1.095 at 20°, boil- 
ing 239° C, the commercial boils 230-234°, with a peculiar characteristic 
odor. It is sparingly soluble in water, but dissolves freely in dilute acids, 
forming well-defined salts of the composition X-HC1. It forms double 
salts with hydrogen platinic chloride and with potassium bichromate. 
The latter is sparingly soluble in water and may be obtained on adding 
potassium bichromate to a solution of the hydrochloride; it melts at 
164-167° C. 



814 ORGANIC SUBSTANCES 

Isoquinolin is a solid melting 22°, boiling 241° C. 

It has a faint odor resembling benzaldehyde. 

Quinolin is quite soluble in hot water, but only slightly in cold water. 
It dissolves easily in all of the ordinary organic solvents and acids. From 
acid solutions or neutral solutions of its salts quinolin is completely dis- 
placed by alkalies, and may be shaken out with ether and recovered. 

It is precipitated by iodin, potassium mercuric iodide, phospho- 
molybdic acid, picric acid, and potassium ferrocyanide in acid solution. 
The picrate forms bright-yellow needles melting 205°. The platino- 
chloride may be crystallized from hot dilute hydrochloric acid, in yellow 
needles containing 2H2O, melting 225°, and from hot water in small needles 
with IH2O, melting 218° C. Quinolin also forms soluble salts with acids, 
the hydrochloride, bisulphate, salicylate, and tartrate. The thiocyanate 
is used medicinally and the double salt of this acid with bismuth is 
marketed under the name " Crurin." 

Quinolin gives no characteristic color reactions with nitric acid or 
sulphuric acid or oxidizing agents. The tests of special value for its 
identification are its precipitation reactions and the melting-points of 
its purified crystalline salts. 

Quinolin and its salts are used in medicine for their antiseptic and 
antipyretic properties. It is used as a mouth wash and gargle, especially 
in diphtheria, as an intestinal antiseptic in dysentery, and for irrigating 
purposes in venereal diseases. It also has a wide use as a vaginal 
douche. The tartrate is given for intermittent fever. 

If it is desired to determine the amount of quinolin in a salt or its 
solution, the base should be liberated with alkali, shaken out with ether, 
the ether solution washed, shaken out with a known volume of standard 
acid, and after separating the acid the excess can be titrated with standard 
alkali, using methyl red as an indicator. One mil N/10 H2S04 = . 004619 
gram quinolin. 

Crurin— Quinolin-Bismuth. Sulphocyanate, (C 9 H 7 N-HCSN) 3 Bi(SCN)3 

It is a fine, brick-red, crystalline powder, with a slight odor of quinolin, 
insoluble in alcohol and ether, but soluble in acetone and slightly so in 
pure glycerin. It is decomposed by water with formation, it is stated, 
of soluble quinolin sulphocyanate, free sulphocyanic acid, and insoluble 
basic bismuth sulphocyanate or bismuth hydroxide. 

When crurin is decomposed by water there is formed an insoluble 
yellow compound and a solution which responds to tests for sulphocyanate 
in that it yields a deep-red color with ferric chloride and a white precipi- 
tate with silver nitrate solution, and to tests for quinolin, in that treatment 
with iodin in potassium iodide solution yields a reddish-brown precipi- 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 815 

tate insoluble in hydrochloric acid; with picric acid solution it yields a 
yellow precipitate; with potassium ferrocyanide solution a green pre- 
cipitate is formed, and with potassium mercuric iodide solution it yields 
a reddish-yellow precipitate, which dissolves on heating. The yellow 
insoluble compound, when treated with potassium iodide solution, becomes 
orange colored, and it responds to tests for bismuth. 

Crurin treated with dilute nitric acid dissolves with formation of a 
solution from which bismuth can be separated by precipitation with 
hydrogen sulphide for quantitative estimation and in which the sulphocy- 
anate content can be determined by titration with standardized silver 
nitrate solution. 

It is useful as a local application for gonorrhea. It is also used in the 
treatment of ulcers of the leg. 

Quinoiodin or Chinoiodin is a chlorin-iodin addition product of 
quinoline, C9H7NICI. It is a yellow powder soluble in alcohol and insolu- 
ble in water, used as an antiseptic in dusting powders and petrolatum 
ointments. 



Iodolin — Quinolin Chloriodomethylchloride, C 9 H 7 NCH 3 C1CH 

,Iodolin is a yellow powder soluble in alcohol and slightly in water, 
also used as an antiseptic. 

Quinolin gives rise to a number of important derivatives. 

yCH * CH2 

Tetrahydroquinolin, Coih^ , boils 245-251° C, soluble in alco- 

\NHCH 2 
hoi and ether and slightly in water and gives a platinochloride which 
melts 200°. This is a secondary base, yielding nitrosamin and capable 
of alkylation. It has strong antiseptic properties. 

Tetrahydroisoquinolin boils 232° and is soluble in alcohol, water, and 
ether. 



8-Hydroxyquinolin, OHC 9 H 6 N 

This is the base of Chinosol, a widely advertised antiseptic. It has a 
characteristic saffron-like odor, melts 75-76°, is volatile with steam, and 
sublimes slowly at the ordinary temperature. It is soluble with difficulty 
in ether and cold water, but dissolves readily in chloroform, alcohol, 
acids, and dilute alkalies. Its acid and alkaline solutions are yellow, 
and a colorless alcoholic solution turns yellow when water is added. 
Its aqueous solution gives a green color with ferric chloride, and a red 
color followed by a black precipitate with ferrous sulphate. 

The hydroxyquinolin sulphonic acids are employed medicinally. 



816 ORGANIC SUBSTANCES 



Vioform — Iodochloroxyquinolin — Nioform 

Vioform is iodo-chlor-hydroxy-quinolin, C9H4N • OH • I • CI. 

It is a voluminous, greenish-yellow powder; crystallizing from glacial 
acetic acid in needles melting at 177 to 178° C, practically odorless, 
and insoluble in water, and slightly soluble in alcohol. 

Vioform contains 41.57 per cent of iodin — it gives a green coloration 
with Millon's reagent or when the alcoholic solution is treated with ferric 
chloride solution. It dissolves with a brown color in concentrated sul- 
phuric acid and the solution evolves iodin on warming. If this solution, 
after driving off the iodin, is diluted with water, chlorine can be demo- 
strated by the usual test with silver nitrate. If a solution of vioform in 
chloroform is shaken with nitric acid, the chloroform acquires a violet- 
red color, and the nitric acid becomes somewhat yellow. 

It is antiseptic, and hemostatic. 

Analgen — 5-acetylamino-8-ethyoxyquicolin 

CH : C(NHCOCH 3 )C-CH=CH 

I II I 

CH=C(OC 2 H 5 ) C— N=CH 

This substance forms colorless crystals, melting 155°, readily soluble 
in alcohol, slightly in water, acidified solution yellowish red. 

The corresponding benzoyl compound is called Benzanalgen, Quinalgen, 
or Laborin, a white, tasteless crystalline powder melting 208°, readily 
soluble in dilute acids. 



Loretin — 7 iodo-8-hydroxyquinolin-5 Sulphonic Acid 

CH : C(S0 3 H) x 

I >C 5 H 3 N 

CI COH x 

Loretin is a colorless, tasteless, reddish-yellow crystalline powder 
which darkens on heating and evolves iodin at 260°. It is soluble in 
alcohol and water and in hot concentrated sulphuric acid without decom- 
position. 

The sodium salt is used as an antiseptic and is sometimes dispensed 
in combination with bismuth subnitrate. Loretin is also combined with 
iodoform, starch, talc, and magnesia, and is a component of many pencils, 
gauzes, etc., used in venereal diseases and for skin affections. The solu- 
ble form is sometimes called " Griserin." 

Argentol or silver quinaseptolate is the silver salt of hydroxyquinolin 
sulphonic acid. It is a yellow powder, soluble with difficulty in water. 






SYNTHETIC ORGANIC NITROGEN COMPOUNDS 817 

Diaptherin is a combination of 8-hydroxy quinolin and p-phenol 
sulphonic acid, green crystals, melting 85°, moderately soluble in water, 
but with difficulty in alcohol. Ferric chloride gives a bluish-green color 
which becomes yellow on adding hydrochloric acid. It is used for rheu- 
matism and as an antiseptic. 

Diapthol — 7-hydroxyquinolin meta Sulphonic Acid 

Yellowish-white crystals melting 295°, fairly soluble in water and use- 
ful as an urinary antiseptic. 

Atophan 
Atophan is 2-phenyl-quinolin-4-carboxyic acid, 

C 9 H5N-C 6 Hs-COOH-2 :4 

Atophan crystallizes in small colorless needles, melting at 208-209° C. 
It is insoluble in water, but readily soluble in alkalies, hot alcohol, and 
boiling glacial acetic acid. It has a slightly bitter taste. 

Atophan is used in the treatment of gout and rheumatic conditions, 

Novatophan 

Novatophan is ethyl 6-methyl-2-phenyl-quinolin-4-carboxylate, 
CH3-C 9 H4N-C6H5COOC2H5, 6:2:4, the ethyl ester of paratophan, 
(6-methyl-2-phenyl-2-quinolin-4-carboxylic acid) . 

It is a slightly yellow, odorless, and tasteless crystalline powder, melt- 
ing at 76°. It is insoluble in water, but readily soluble in alkalies, hot 
alcohol, and strong acids. 

If 0.1 to 0.2 gram novatophan is boiled for a short time with 0.5 mil 
sodium hydroxide solution, then 5 mils iodin test solution added and 
again heated, the odor of iodoform will be apparent. 

When dissolved in concentrated sulphuric acid, a light-yellow solu- 
tion results which on the addition of bromin water yields a reddish- 
yellow precipitate. 

On adding ferric chloride to an alcoholic solution of novatophan a 
yellow, not a brown color, is produced. 

Paratophan 

Paratophan is methyl-atophan, 6-methyl-2-phenyl-quinolin-4-car- 
boxylic acid, CH 3 C 9 H 4 N • C 6 H 5 • COOH, 6:2:4. 

It is a yellow crystalline powder melting at 228Vsoluble in alcohol, 
ether, chloroform, and alkalies, but insoluble in water. It has a slightly 
bitter taste and a faint odor. 



818 ORGANIC SUBSTANCES 

Wiien dissolved in concentrated sulphuric acid a light-yellow solu- 
tion results, which yields a light-yellow precipitate on the addition of 
bromin water. 

If ferric chloride solution is added to an alcoholic solution of para- 
tophan, a brown color is produced. 

If paratophan is heated above its melting-point carbon dioxide is 
liberated and methyl-phenyl-quinoline, CH3C9H5N • C6H5, melting at 68° 
is produced. 

Thalline — 6-methoxytetrahydroquinolin 

Thalline is prepared by heating p-aminoanisole and p-nitroanisole 
with glycerol and sulphuric acid and subsequent reduction. The free 
base crystallizes in colorless prisms, melting 42°, boiling 283°, pungent, 
sparingly soluble in water but readily in alcohol, ether, chloroform, and 
benzol. 

Thalline is usually marketed as the sulphate which is readily soluble 
in water. An aqueous solution gives precipitates with the general alka- 
loidal precipitants and alkalies; ferric chloride added to very dilute solu- 
tions produces a yellow color, changing to emerald green and finally pass- 
ing to red; and a green color may also be obtained with gold chloride, 
mercuric chloride, silver nitrate, chlorine water, and in acid solution with 
bleaching powder and potassium ferrocyanide. /3-naphthaquinone in 
aqueous solution treated with a solution of thalline sulphate and a drop 
or two of sodium hydroxide yields a red color, made more brilliant by 
nitric acid and soluble in ether or chloroform. 

The free base dissolves in sulphuric acid without color, but the addition 
of nitric acid causes a deep-red color changing to a yellowish red. Sul- 
phuric acid containing sugar produces a red color. 

The sulphate is used in yellow fever. An addition compound of thai- 
line and iodin is used for carcinoma. 

Orexine — 3-phenyl-3, 4-dihydroquinazolin 

The base of orexine is a derivative of a quinazoline and is obtained 
by treating formanilid sodium with o-nitrobenzyl chloride and reducing 
the ortho-nitrobenzylformanilid, 

C 6 H4< >NC 6 H 5 

X CH 2 — / 

Orexine is the hydrochloride of the base, but the term is applied indis- 
criminately to the base and the hydrochloride, for there is a substance 
called orexine tannate which is claimed to be a tannate of the base. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 819 

The base is soluble in alcohol, ether, and chloroform, but dissolves 
in acids and is thrown out of acid solution by alkalies. A solution of the 
base is precipitated by mercuric chloride, the deposit dissolves in hot 
water, but crystallizes out on cooling. The precipitate with potassium 
bichromate has similar properties. Bromin water is decolorized, and 
a yellow amorphous precipitate thrown down; tannin produces a pre- 
cipitate and permanganate undergoes reduction. The solid substance 
when heated with zinc dust evolves phenyl-isocyanide, and the residue, 
on treatment with hydrochloric acid, filtering and adding calcium hypo- 
chlorite solution, gives the blue color characteristic of anilin. A solu- 
tion of the base in concentrated sulphuric acid is colored green by nitric 
acid, a reddish color appearing on the edges. 

Orexine hydrochloride crystallizes with 2 molecules of water, 

G14H12N2HCI+2H2O 

It produces violent sneezing, and in medicine is used as a tonic and 
stomachic. 

The tannate is almost insoluble in water, but dissolves in dilute hydro- 
chloric acid. It gives the characteristic reaction of a tannate, and the 
base may be precipitated by alkali from a solution in 30 per cent acetic 
acid. 

Phenylene-diamines — Diaminobenzenes, C 6 H 4 (NH 2 )2 

There are three modifications, ortho, melting 102-103°; meta, melting 
63°; para, melting 140°; boiling respectively 252°, 287°, 267°. Sodium 
nitrite, added to neutral aqueous solutions, give with separation 
of amino-azo-phenylene as a colorless oily liquid, with m-yellow or brown 
color or precipitate of triamino-azobenzene, with p- no color. The meta 
is easily removed from alkaline solutions by ether. The hydrochloride 
is a well-defined salt, known commercially as Lentin. 

The meta-compound is used in acute bowel trouble where an anti- 
septic is required. 

The para is used as a hair dye. A solution of the base in weak potas- 
sium hydroxide when mixed with hydrogen peroxide develops a black 
color, and with ferric chloride a brown. 

In case of poisoning caused by hair dyes, this substance or a diamino 
toluene may be suspected. 

Paraphenylene diamine is prepared directly from acetanilid by nitra- 
tion and subsequent reduction. This fact should be borne in mind by 
the control chemist who may be called upon to testify in cases involving 
the analysis of a preparation containing the base. It is of course question- 
able whether a hair dye is a medicine or a drug, being more properly a 
cosmetic, which is not subject to the drug act as it is at present interpreted. 



820 ORGANIC SUBSTANCES 



Methylene Blue, Ci 6 Hi 8 N 3 SCl. Tetramethylthionine 

Methylene blue is an oxidation product of dimethyl para-phenylenedi- 
amine in hydrogen sulphide solution. The medicinal product should 
be free from zinc chloride. It is a dark-green or red-brown bronzy powder, 
readily soluble in water to a deep-blue solution, and is removable from 
an alkaline solution with ether. It dyes cotton mordanted with tannin 
a blue color which is fast to light and soap. 

Methylene blue has attained its greatest reputation as a remedy for 
gonorrhea, and is usually dispensed in capsules or pills. It will be found 
by itself and in combination with copaiba, and oils of santalwood and 
cinnamon, methyl salicylate, and haarlem oil. 

It is the ingredient of kidney remedies advertised to the laity, the 
literature of which admonishes the patient to observe the urine after 
taking, and if it acquires a greenish color he may know the remedy is 
doing its work. These remedies, usually in the pill form, may contain 
in addition to methylene blue, buchu, juniper, potassium acetate or nitrate, 
copaiba, cubeb, methyl salicylate, aloes, extracts of Eupatorium, triticum, 
Pichi, Chondrodendron tormentosum, Hydrangea, cornsilk, and others. 



Toluylene-diamines — Diaminotoluenes, C 6 H 3 (CH 3 ) (NH 2 ) 2 

The substances occur in two types, the alpha and beta. The former 
is the ortho-para modification (1-2-4), melting 99°, and the latter the 
meta-para (1-3-4). They closely resemble the phenylene diamines. 

Comparative reactions of these two substances in neutral or slightly 
acid solutions have been reported as follows : 

Ferric Chloride. Alpha — No change at first, orange on long standing. 

Beta — Wine-red color. 
Potassium Bichromate. Alpha — Yellowish-brown color. 

Beta — Reddish-brown precipitate. 
Potassium Ferricyanide. Alpha — Olive-green crystalline plates. 

Beta — Dark-red color. 
Bromin Water. Alpha — Yellowish-white precipitate. 

Beta — Brown flocks, magenta-red solution. 
Potassium Nitrite. Alpha — Golden-brown color, dilute. Brown precipi- 
tate when concentrated. 

Beta — Salmon-red precipitate. 
Bleaching Powder Solution. Alpha — Reddish-brown color, light brownish- 
yellow precipitate. 

Beta — Dark-red color. Olive-green precipitate. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 821 

These bodies are used in hair dyes. The treatment consists of either 
a solution of the diamine in alkali; or an amount of the crystalline sub- 
stance sufficient for an application and another bottle containing a reagent 
which, when mixed with it, will bring out the requisite color. 



AMIDES 

Amides may be considered as substituted ammonias in which the 
hydrogen has been replaced by an acid radicle. There are three classes, 
primary, secondary, and tertiary. 

H 

N— COCH3 HN=(COCH3) 2 N(COCH3) 3 

H 

Acetamide, CH3CONH2, may be obtained by the interreaction of 
acetyl chloride or acetic anhydride with ammonia, or by distilling ammo- 
nium acetate in a stream of dry ammonia gas. It crystallizes in colorless, 
deliquescent needles, melting 80-82° and boiling 222° C. It is almost 
odorless when pure, but as usually found has a strong mousy odor. It 
dissolves in water and alcohol and when heated with mineral acids or 
alkalies is decomposed into acetic acid and ammonia or their salts. On 
distillation with phosphoric anhydride it loses a molecule of water and 
is converted into methyl cyanide or acenitrile, 

CH3CONH2 = CH3CN+H2O. 



Neuronal— Diethylbromacetamide, Br(CoH 5 ) 2 CONH 2 

Neuronal is a white crystalline powder, with a camphoraceous odor 
and a bitter, cooling taste. It melts 66-67° C. and is somewhat soluble 
in water, readily in alcohol and ether. It is used as an hypnotic. 

When heated with dilute sodium hydroxide, sodium bromide and 
cyanide are produced and diethylketone set free. 



Salicylamide, C 6 H 4 (OH)CONH 2 

Salicylamide is a colorless crystalline substance, melting 138° C, 
soluble in alcohol, ether, chloroform, and slightly in water. 

Tt is used as a remedy for rheumatism and fevers and has antiseptic 
properties like salicylic acid, which it resembles in those reactions which 
are characteristic of the phenolic group. 



822 ORGANIC SUBSTANCES 



pmiy 



Valeric Acid Diethylamide, CH 3 CH 2 CH 2 CH 2 CO 

This body, known as Valyl, is a colorless liquid with a methyl-like 
odor, boiling 210° C, soluble in alcohol, ether and somewhat in water. 

It has hypnotic and antineuralgic properties, and is employed in 
nervous troubles. 



.NH 2 



Urea and Its Derivatives 



Urea, C=0 , or carbamide, is the amide of the dibasic carbonic 

\nh 2 

acid, C=0 . It is a substance of great importance in physiological 

\)H 

chemistry, and methods for its detection and determination have been 
the subject of a vast amount of research. It is used in a limited way in 
medicine, but some of its derivatives have an extended use and are of 
considerable interest to the drug chemist. 

Urea is used in tuberculosis and as a diuretic. In renal calculus it 
is sometimes given in comparatively large doses. 

Urea forms transparent, colorless, somewhat hygroscopic prisms, odor- 
less, or with a faint odor suggestive of urine, melting at 132° and decom- 
posing at 150-160° with evolution of ammonia and formation of biuret. 
It may be distilled in vacuo at 135° C. 

It is very soluble in alcohol and cold water and much less in hot water. 
It is but slightly soluble in ether, and the other organic solvents have little 
or no action. 

On fusion with caustic alkalies, ammonia is evolved and a carbonate 
is formed. On heating with strong mineral acid carbon dioxide is given 
off and a salt of ammonia produced. Pure concentrated nitric acid com- 
bines with urea without decomposing it, but if nitrous acid is present, 
nitrogen and carbon dioxide are evolved. 

Urea forms salts which are dissociated by water, the nitrate and 
oxalate are easy to prepare, and the latter is but sparingly soluble in cold 
water. 

Urea is not precipitated by the usual alkaloidal reagents, nor does 
it give color tests with the oxidizing agents. When heated at 160° for 
some time, the residue dissolved in water and made slightly alkaline with 
sodium hydroxide, the addition of a dilute solution of cupric sulphate 
will produce a violet or red color. This is known as the biuret test. It 
is precipitated by mercuric nitrate from a solution free from chlorides 
and it is not precipitated by mercuric chloride. The mercuric nitrate 






SYNTHETIC ORGANIC NITROGEN COMPOUNDS 823 

compound may be used to good advantage in the purification of urea, 
because it can be separated from the solution, washed and decomposed 
by hydrogen sulphide with liberation of the base. 

Adalin 

Adalin, C(C 2 H 5 )2Br • CONH • CONH 2 , is bromdiethyl-acetyl-carbamide. 

It is an almost colorless and odorless crystalline powder, with a melting- 
point of 116° C, which dissolves readily in alcohol as well as in the other 
ordinary organic solvents. It is difficultly soluble in water. 

It is used as a sedative and mild hypnotic. 

Bromural 

Bromural, (CH 3 -CH(CH 3 )CHBrCO)HN-CONH 2 , is 2-mono-brom- 
isovaleryl-urea. 

It forms small, white, almost tasteless needles which are easily soluble 
in hot water, ether, alcohol, and alkalies, but less readily in cold water. 
It sublimes on heating and melts in the neighborhood of 145° C. 

Bromural can be precipitated from a 10 per cent sodium hydroxide 
solution with acids. The presence of bromin may be demonstrated by 
fusion with sodium carbonate and potassium nitrate and testing for a 
bromide with silver nitrate solution. On heating the alcoholic solution 
of bromural with sodium ethylate for several hours on the water-bath, 
sodium bromide will precipitate. If this is filtered off and the filtrate 
evaporated, a crystalline mass will remain which can be recrystallized 
from water. This is dimethylacrylic acid, melting at 280° C. 

If 1 gram bromural is boiled for about one minute with 10 per cent 
solution of sodium hydroxide, ammonia obtained from the urea will be 
given off. If the hot liquid is then cooled, acidified with nitric acid and 
extracted with ether, and the ether evaporated, an oily fluid, 1-brom- 
isovaleric acid, which has the specific odor of valeric acid, will remain. 

The biuret reaction cannot be obtained. On melting bromural and 
adding concentrated sodium hydroxide solution and copper sulphate, 
no color reaction will take place. 

Bromural is a nerve sedative. 

| Thiosinamine^-Allyl Sulphocarbamide — ^llyljrhiourea^ — Rhodaline 

Thiosinamine is allyl-thio-urea, (NH 2 ) • CS • NHCH 2 • CH : CH 2 . 

It forms colorless crystals, having a slight alliaceous odor and bitter 
taste and melting at 74° C. It is moderately soluble in water, but is 
decomposed by this solvent. It is soluble in about 3 parts of alcohol 
and readily soluble in ether. 



824 ORGANIC SUBSTANCES 

It is used by hypodermic injection in lupus, chronic glandular tumors, 
and by mouth in stricture, corneal opacity, chronic deafness. 

Fibrolysin 

Fibrolysin, (NH 2 • CS • NHCH 2 • CH : CH 2 )+C 6 H4(OH)(COONa), is a 
sterilized solution of a double salt of thiosinamine and sodium salicylate 
containing 15 per cent of the double salt. 

The tests are those of thiosinamine and sodium salicylate. 

Maretin— Metatolylhydrazine Carbaminate, CeH^CHsNHNHCONHa 

Maretin forms colorless, lustrous crystals, melting 183-184°, some- 
what soluble in alcohol, but only slightly in ether, chloroform, and water. 
It is an antipyretic. 

Ethyl Carbamate — Urethane 

When urea or its nitrate are heated to 100° C. with alcohol, ethyl 
/ OC 2 H 5 

carbamate, C=0 , is formed. It is a colorless c^stalline substance, 

\nh 2 

with a faint peculiar odor and a saline taste, melting 48-50° and boiling 
180° C. It is readily soluble in water, alcohol, ether, chloroform, and 
glycerin. On warming with concentrated sulphuric acid, carbon dioxide 
is evolved and alcohol and ammonium bisulphate remain in solution. 
On warming with concentrated alkali, ammonia gas is given off. An 
aqueous solution treated with sodium carbonate and a little iodin, will 
deposit iodoform on warming. Its aqueous solution gives no precipi- 
tate with nitric acid, mercuric nitrate, or oxalic acid. 

Urethane is used as a sedative, hypnotic, and antispasmodic, and will 
be found in remedies for insomnia, nervousness, and tetanic poisons. 

Urethane forms a compound with chloral having the composition 
CCl3CH(OH)(NH)COOC 2 H 5 , and known as chloralurethane, furalium, 
ural, or uraline. It melts 103° C. and is soluble in alcohol and ether. 
This substance is also used as an hypnotic. 

/_Jpthylidene urethane, CH 3 CH(CO(NH)OC 2 H 5 ) 2 , is a crystalline body 
melting 125-126° resulting from the action of hydrochloric acid on a solu- 
tion of urethane in acetaldehyde. 
/OC 2 H 5 

Phenyl urethane, CO , is closely allied to urethane. It is 

NsiHCeHs 
called Euphorin. The product is prepared b}^ the action of anilin on 
the ethyl ester of chloroformic acid. It occurs in the form of colorless 









SYNTHETIC ORGANIC NITROGEN COMPOUNDS 825 

needles or a white powder with a faint odor and a clove-like taste, melting 
50-51°. It is but slightly soluble in water, but soluble in dilute alcohol, 
strong alcohol and ether. 

It is used internally for rheumatism, sciatica, and headache, and 
externally as a dusting powder for venereal sores, skin diseases, etc. 

Hedonal — Methylpropylcarbinol Urethane 

Hedonal is pentan-2-ol urethane, CH 3 • CH 2 • CH 2 • CH(CH 3 )0 • CO • NH 2 . 

It is a white, crystalline powder, having a faint aromatic odor and taste, 
melting at 74° C, and boiling at 215° C. It dissolves in 120 parts of water 
at 37° C. but is more soluble at higher temperatures and is readily soluble 
in alcohol, ether, chloroform, and other organic solvents. It is readily 
volatilized with the vapors of water or alcohol, and when boiled with 
alkalies is split up into its constituents, methylpropylcarbinol, ammonia, 
and carbon dioxide. 

On boiling with dilute sodium hydroxide, ammonia is evolved and 
recognized by the odor and the usual reactions; if then an aqueous solu- 
tion of iodin in potassium iodide is added, and the mixture allowed to 
cool, the odor of iodoform derived from the alcohol is distinctly manifested. 

Hedonal appears to have a greater hypnotic effect than ethyl car- 
bamate, 

Neurodin — Acetylparaoxyphenylurethane 
/OC2H5 

c=o 

^NHOCOCHsCeHi 

Neurodin may be considered as a derivative of amido phenol as well 
as of urea. It forms colorless crystals, melting 87° C, which are slightly 
soluble in water. 

It is used as an antipyretic and antineuralgic. 

Thermodin is claimed to be acetyl paraethyoxyphenyurethane, hence 
it should stand in close relationship to the last-named substance. 

Barbituric Acid and Its Derivatives 
When urea and malonic acid react under proper conditions, barbi- 
'NH|ITOH|CO 



turic acid results, C=0 ")CH 2 . In this body the central 



NH H OH CO 



hydrogen atoms have acid properties. 



826 ORGANIC SUBSTANCES 

Veronal — Diethyl Malonyl Urea 
Veronal is diethyl-barbituric acid, 2, 4, 6-trioxy-5-diethyl pyramidin, 
.NHCO C 2 H 5 

co Nc/ 

\nH-CO C2H5 

a ureide derived from diethylmalonic acid, COOHC^Hs^COOH, and 
urea, CO(NH 2 ) 2 . 

It is a white, crystalline powder, melting at about 188-191° C, sub- 
liming on heating, odorless and faintly bitter. It is soluble in about 
150 parts of cold water and in about 12 parts of boiling water. It is quite 
soluble in ether, acetone and ethyl acetate ; also slightly soluble in chloro- 
form, petroleum benzine, acetic acid, and amyl alcohol. It forms salts 
with alkalies which are soluble in water. 

Prolonged heating with sodium carbonate solution liberates ammonia. 
Denige's reagent produces a white precipitate; Millon's reagent produces 
in solution acidulated with nitric acid a precipitate soluble in excess of 
the reagent. 

When added to potassium hydroxide, fused in a nickel crucible, and 
heated for two minutes, the cold mass on dissolving in water should give 
a blue precipitate with ferrous sulphate; on adding excess of acid and 
shaking with ether, an oily mass is extracted, having the odor of rancid 
butter, soluble in water, and giving a wine-red color with ferric chloride. 

A so-called salt of the above ureide with sodium is marketed as Veronal- 
sodium, as Medinal and probably other designations. It is soluble in 
5 parts of water. Veronal is an hypnotic. 

Proponal — Bipropylmalonylurea 
/NH-CO C3H7 

0=0 

\ 



\ 



C3H7 



Proponal is closely allied to veronal, dipropylmalonic acid being used 
in the synthesis instead of the diethyl compound. It forms colorless 
crystals slightly soluble in cold water, more readily in hot, and easily in 
alcohol, ether, chloroform and alkalies. It melts 14£°- 

It is used for the same purposes as veronal. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 827 

Luminal — Phenyl-ethyl-barbituric Acid — Phenyl-ethyl-malonyl-urea 

Luminal is phenyl-ethyl-barbituric acid, 2, 4, 6-trioxy-5-phenyl-ethyl 
pyramidin, 

/NH-CO C 6 H 5 

do >c/ 

\nHCO C2H5 

Luminal is a white, odorless, slightly bitter powder. It is almost 
insoluble in cold water, slightly soluble in hot water and readily soluble 
in alcohol, ether, and chloroform, and in alkaline solutions. It crystal- 
lizes from boiling water to lustrous leaflets, and is precipitated unchanged 
by acids from its alkaline solutions. It melts at 173-174° C. 

If about 0.3 gram is shaken for a short time with 1 mil of normal 
sodium hydroxide and 5 mils of water, and the mixture filtered, the filtrate 
will yield white precipitates on the addition of mercuric chloride and of 
silver nitrate solutions. 

If about 1 gram is boiled for five minutes in 10 mils of a 50 per cent 
solution of sodium rrydroxide, ammonia will be evolved. 

If about 1 gram is dissolved in 5 mils of normal sodium hydroxide 
and the solution heated for four hours on a boiling water-bath, the evapo- 
rated water being replaced, crystals of pheny-acetyl-urea will separate 
on cooling. When recrystallized from dilute alcohol these crystals melt 
at 147° C. 

Luminal is used as an hypnotic in nervous insomnia and conditions 
of excitement of the nervous system. 

Adrenalin — Epinephrin 

The suprarenal glands of sheep and other animals contain a basic 
substance which has a strong physiological action causing a rise in the 
blood pressure, and is used in hemorrhage, catarrhal, and congestive 
conditions. The blood pressure raising principle has been separated and 
purified and is now a commercial article being sold under several names, 
adnephrin, adrenalin, adrin, epinephrin, supracapsulin, suprarenalin, etc. 
Some controversy has arisen as to the name which was first applied to 
this substance before its composition was known, but the merits of the 
case need not be discussed here. 

The active principle is usually marketed in a weak solution (1 : 1000) 
of the hydrochloride, and as it is very unstable, some preservative such 
as chloretone is added to the solution, and it is further inertized by satu-^ 
rating with carbon dioxide. There is also a large demand for the desic- 
cated glands and their extract. 



828 ORGANIC SUBSTANCES 

The active principle is sometimes combined with cocain and with 
spartein in tablets, it is also formulated with sodium chloride and boric 
acid in order to yield a non-irritant solution. It is put up in oily mix- 
tures to be used as a nasal spray and in ointments and suppositories. 
The oily inhalants usually contain alcohol. Its use is extending to com- 
plex lotions and ointments, but it is of such an unstable nature that the 
value in these products is questionable. 

Epinephrin is 1, 2-dihydroxy-4 2 -methylamino ethyl-4 1 -ol benzene, 
CeHs (OH) 2 (CHOH • CH 2 NHCH 3 ) . 

It is a finely crystalline white or yellowish powder, odorless and slightly 
bitter. It melts at 201-207° C, turning brown and decomposing at the 
higher temperature. 

It shows a slightly alkaline reaction to moistened red litmus paper. 
It is almost insoluble in cold water, more readily in hot water. It is 
difficultly soluble in alcohol and insoluble in ether. The colorless aqueous 
solution is easily oxidized on contact with the air, becoming pink, then 
red, and eventually brown. The base reacts with acids to form salts 
which are readily soluble in water; it is also soluble in the fixed alkalies, 
but not in ammonium hydroxide or in solutions of the alkaline carbon- 
ates. The following reactions are the most characteristic: The addition 
of ferric chloride to a solution of the alkaloid produces a beautiful emerald- 
green color which by careful addition of caustic alkali becomes purple, 
and then carmine red. Strong acid prevents the reaction with ferric 
chloride, limiting the change of color to a dirty yellowish-green. It gives 
a vivid pink color with iodin. The alkaloid reduces silver salts and 
gold chloride very energetically, and the liquid turns red. A drop of 
1 : 10,000 solution instilled into the eye will, within a few seconds, pro- 
duce a pallor of the conjunctiva. 

L-Suprarenin Synthetic 

L-suprarenin synthetic is epinephrin produced synthetically accord- 
ing to the method of Stolz and Flaecher. 1 

It is a white, odorless powder nearly insoluble in water, alcohol, and 

ether. It melts at 211-212°. It has the power of rotating polarized 

light to the left: 

, , 19.6° K1 AO 
(a) -g-= -51.4 . 

It has the chemical and physical properties and physiologic effect of 
natural epinephrin obtained from suprarenal glands. 

Methods for the determination of adrenalin in order to arrive at a 
1 Ztschr. f. physiol. Chem., 58, p. 189. 



SYNTHETIC ORGANIC NITROGEN COMPOUNDS 829 

standard for desiccated suprarenal glands, have been the subject of much 
study. 

Hale and Seidell published a method based on a color comparison 
with platinic chloride and cobalt chloride, Folin, Cannon, and Denis 
recommended the use of phosphotungstic acid, and later Seidell sub- 
stituted gold chloride for platinic chloride in his original method. These 
procedures in the order of their appearance are included. 

Method of Hale and Seidell. 1 — .01 gram of the desiccated gland is 
treated with 5 mils dilute hydrochloric acid and 5 mils potassium iodate 
solution 0.2 per cent, heated just to boiling, allowed to stand fifteen 
minutes, filtered and the color compared with a series of standards. The 
latter are made up from a mixture of potassium platinic chloride and 
cobalt chloride solutions, which develop a color similar to that given by 
epinephrin and potassium iodate and which have been previously stand- 
ardized against the ash-free active principle. The yellowish extractive 
matter present in the aqueous solution interferes with the test, but may 
be obviated by using a small quantity of the sample and not diluting. 

Method of O. Folin, W. B. Cannon, and W. Denis. 2 — The glands are 
extracted with N/10 hydrochloric acid and water, the mixture being 
finally heated to boiling. After the addition of sodium acetate solution 
and further boiling, the mixture is diluted with water and filtered or centri- 
f aged to obtain a clear extract. As a rule, 100 mils of extract are obtained 
from 2 grams of gland. Five mils are put into a 100-mil flask and 1 mil 
fresh uric acid solution containing .0010 gram of the acid is put into 
another flask. A special reagent is then made as follows: 100 grams 
sodium tungstate and 80 mils of 85 per cent phosphoric acid are boiled 
gently with 750 mils water for two hours and then made up to 1 liter. 
Ttt-o mils of the reagent and 20 mils of saturated sodium carbonate solu- 
tion are added to each of the 100-mil flasks, allowed to stand for a few 
minutes, shaken and made up to the mark. The colors of the deep-blue 
liquids are compared in a Duboscq colorimeter. The amount of epine- 
phrin can be calculated from the fact that it produces three times as much 
color as an equal weight of uric acid. 

Johannesohn used this method for estimating epinephrin in ordinary 
commercial preparations, but found it inapplicable in the presence of 
novocain or alypin. 

Method of A. Seidell. 3 — 0.01 gram of the sample is shaken with 0.005 
gram of manganese dioxide and 10 mils water and after standing one 
hour the mixture is filtered into a test-tube and the color compared with 
that of a color standard in a tube of similar dimensions. The color 

l Am. J. Pharm., 83, 551. 

2 J. Biol. Chem., 1913, 13, 472. 

3 J. Biol. Chem., 1913, 15, 197. 



830 



ORGANIC SUBSTANCES 



standards are prepared from solutions of cobalt chloride 2 per cent (with 
1 mil cone. HC1) and gold chloride 0.1 per cent as shown in the following 
table : 





Color Standard 


Epinephrin 










Cobalt Solution 


Gold Solution 


Water 


Gram 


Mils 


Mils 


Mils 


.00001 


1.15 


.70 


8.15 


.00002 


1.85 


.95 


7.20 


.00003 


2.40 


1.10 


6.50 


.00004 


2.95 


1.25 


5.80 


.00005 


3.50 


1.30 


5.20 


.00006 


4.05 


1.35 


4.60 


.00008 


5.15 


1.55 


3.30 


.00010 


6.30 


1.75 


1.95 



The oxidation product of epinephrin which results when a solution 
of the base is treated with an excess of ammonia, is soluble in amyl alcohol, 
but does not dissolve in chloroform, ether, or petroleum ether. It gives 
a bluish-green color with a very dilute solution of potassium ferricyanide 
containing ferric chloride, and a blue color with an ammoniacal solution 
of phosphomolybdic acid. It does not respond to the other character- 
istic reactions for epinephrin according to Venturoli and Gailbrani, 1 
who have made a study of the oxy body. 



Tyramine 
Tyramine is para-hydroxy-phenyl-ethyl-amine hydrochloride 
OH ■ C 6 H 4 • CH 2 • CH 2 • NH 2 • HC1 

The base para-hydroxy-phenyl-ethyl-amine was first isolated by 
Barger from ergot and also prepared synthetically by him by the reduc- 
tion of para-hydroxy-acetonitrile with sodium in alcoholic solution. It 
is chemically and physiologically related to epinephrin (C6Hs(OH)2 
(CHOHCH2NHCH3). 

Tyramine occurs as an almost white crystalline powder, easily soluble 
in water, forming a neutral solution. 

Taken internally or injected subcutaneously tyramine increases the 
blood pressure; for this reason it can be used in shock or collapse; it is 
also claimed to be valuable for producing post-partum contraction of 
the uterus. It is useless as a local hemostatic. 

1 Giom. Farm. Chun., 1911, 60, 97. 



CHAPTER XXI 
ANILIDES AND PHENETIDINS 

ANILIN, C 6 H 5 NH 2 

Anilin is an important substance in the chemistry of medicinal 
products, but it is seldom used itself as a drug. Its properties are anti- 
septic. It is one of the intermediary products formed in the quantitative 
estimation of acetanilid, and it results in the hydrolysis of some closely 
allied chemicals whose identity it may help to establish. Hence it. is 
advisable to be thoroughly familiar with the properties of anilin and 

/OK 
also the analogous compounds, amino phenols, C6ELi\ , which are 

X NH 2 
obtained by the reduction of nitro phenols, while anilin comes from 
nitro benzol. 

The pure substance is colorless, but it becomes yellow or brown on 
exposure to light and air due to oxidation. It is of oily consistency, 
sp. gr. 1.0254 at 15° C, solidifying 6°, boiling 184°. It is but slightly 
soluble in water, but dissolves easily in alcohol, ether, chloroform, acetone, 
and acid liquids. It is thrown out of an acid solution by excess of alkali, 
and can be recovered unchanged by shaking with ether. It dissolves 
sulphur, phosphorus, and colophony, but not caoutchouc nor copal. It 
combines readily with bromin to form tribromanilin, and the aqueous 
solution of anilin gives an immediate precipitate if treated with bromin 
water or bromide-bromate reagent. 

Anilin is a strong base, forming well-defined stable salts with acids 
of the composition of CeHjN-HR. A cold aqueous solution of an 
anilin salt is converted into a salt of diazo benzene when treated with 
nitrous acid or a nitrite and mineral acid, and on subsequent boiling 
phenol is produced with evolution of nitrogen. 

Anilin gives the well-known and disagreeable carbylamine reaction 
when warmed with chloroform and potassium hydroxide. With sulphuric 
acid and manganese dioxide a purple color results, and purplish shades 
are given under the same conditions in presence of other oxidizing agents. 
The reactions somewhat simulating those of strychnin. Nitric acid gives 
a purple color in the cold, changing to indigo blue and then to greenish 
blue on heating over the steam-bath, then as the reaction becomes more 

831 



832 ORGANIC SUBSTANCES 

violent a brownish-black shade develops. The residue gives an aromatic 
odor with alcoholic potash. 

When a small amount of anilin is treated with an aqueous solution 
of carbolic acid followed by a solution of bleaching powder, yellow streaks, 
changing to greenish blue, are obtained. If anilin is treated with 2 to 
3 drops of dilute solution of bleaching powder 1 in 200, in such a manner 
that the two liquids do not mix, a purple or blue color will form at the 
junction of the liquids. 

Anilin combines with equivalent amounts of dilute and concentrated 
acids, except nitric to form salts, and it furthermore yields stable deriv- 
atives on treatment with excess of acids and subjecting to higher tempera- 
tures, thus with sulphuric acid a series of annno-benzene sulphonic 
acids, C6H4 • NH2SO3OH, result, and with acetic acid, acetanilid, 
C 6 H 5 NH-COCH 3 , is formed. 

Nitric acid, when dilute, converts anilin to nitranilins and when con- 
centrated to quinone and other substances. 

If a solution of anilin in concentrated hydrochloric acid 1 in 3 diluted 
with an equal volume of water is diazotized with sodium nitrite and the 
diazotized solution saturated with dry sodium chloride and poured off 
from any undissolved salt, the ice-cold solution, when treated with stan- 
nous chloride in concentrated hydrochloric acid, 6 to 2 J (in proportion 
to the anilin used) will separate out phenylhydrazine hydrochloride 
after several hours standing. 

This reaction is of interest to the drug chemist, from a theoretical 
point of view, because antipyrin can be prepared from phenylhydrazine. 
We have thus an anomalous situation in control work for antipyrin, 
though not an inhibited drug, can be obtained directly from anilin, 
the base substance of acetanilid, while acetphenetidin, which is not 
made from anilin at all, but from amino phenol, is classed as a derivative 
of acetanilid. 

Bromamide 

Bromamide is the hydrobromide of tribromanilin, CelTtBrsNHBr. 
It forms colorless, odorless, tasteless needles, melting 154-155° C, soluble 
in chloroform, ether, and hot alcohol, but insoluble in water. It is used 
as an antipyretic, antineuralgic, and antirheumatic. 

Paraiodanilin, C 6 H 4 NH 2 1. 1-4 

This a colorless to bluish crystalline substance, melting 60° C, soluble 
in alcohol, ether, and chloroform. Its hydrochloride is yellowish, soluble 
in alcohol and slightly in water. It is used as an antiseptic. 

The homologues of anilin have similar properties. 



ANILIDES AND PHENETIDINS 



833 



There are three toluidines and six xylidines; they are all liquids at 
the ordinary temperature except para-toluidin. Their identification or 
determination becomes a matter of moment when one is working with 
an abnormal specimen of some anilin derivative which is suspected of 
containing derivatives of its homologues. The acetyl derivatives of 
some of them are credited with possessing antipyretic properties and 
may sometimes be substituted for acetanilid. 





Melting-point 


Boiling-point 


Melting-point of acetyl 
derivat've 


Ortho-toluidin 


below -20° 


199.5° 


114° 


w-toluidin 


below -13° 

+45° 


197 
198 
223 


107 


p-toluidin 


65-66 


■u-ortho xylidin 1 : 2.3. . 


134 


a-ortho xylidin 1 : 2.4. . 


+49° 


226 


99 


w-meta xylidin 1 : 3.2. . 




216 


176.8 


a-meta xylidin 1 : 3.4. . 




212 


129 


s-meta xylidin 1 : 3.5 . . 


g 


220 


140.5 


Para xylidin 1 : 4.2 . . 




213.5 


139 



ACETANILID, C 6 H 5 NHC 2 H 3 

The anilides are derivatives of anilin in winch one or more of the 
hydrogen atoms of the amino group are replaced by acid radicles. The 
homologues yield similar derivatives and we therefore have toluides, 
xylidides, etc. 

Unquestionably the most important derivative of anilin in the realm 
of pharmaceutical chemistry is acetanilid. Tins substance, which also 
goes by the name of phenylacetamide and antifebrin, is sold in enormous 
quantities as an antipyretic and analgesic and in various combinations 
with cafTein, sodium bicarbonate, and bromides, occurs in by far the largest 
proportion of the headache mixtures sold on the market. Acetanilid 
is also used as an antirheumatic, anesthetic, and antiseptic, and for the 
latter purpose it will be found in hydrogen peroxide. 

Acetanilid is usually dispensed in tablets or powders. The com- 
binations include acetanilid with cafTein and bromides, usually sodium; 
with cafTein, bromides and sodium bicarbonate, sometimes with the addi- 
tion of codein or heroin or quinin sulphate; with salol; with morphin; 
with quinin sulphate, with Gelsemium; with bromides, hyoscyamin and 
digitalin; with cafTein and monobromated camphor; with salicylates, 
Gelsemium, monobromated camphor and hyoscyamin; with bromides, 
cafTein, Hyoscyamus and morphin; with quinin, Hyoscyamus, arsenic, 
strychnin and Cannabis; with quinin, bromides, aloin, cascara, and 
Capsicum. 



834 ORGANIC SUBSTANCES 

Acetanilid will also be found in liquids usually of the elixir type, 
where it is combined with bromides and caffein, to which are often added 
codein, Gelsemium, salicylates, antipyrin, and other drugs in combina- 
tions similar to those occurring in tablets. 

Acetanilid is obtained by boiling a mixture of molecular proportions 
of anilin and glacial acetic acid under a reflux, and recrystallizing the 
resulting product out of water. It forms laminary crystals having a 
smooth feel, recalling that of boric acid, subliming at the temperature of 
the steam-bath, melting 111-113°, depending on the condition of its purity 
and distilling unchanged at 295°. It dissolves sparingly in cold water, 
but is fairly soluble in boiling water and readily dissolved by alcohol, 
ether, chloroform, or benzol. It is somewhat soluble in petroleum ether, 
and is removed from acid solutions by that solvent. 

Acetanilid is a weak base and does not form stable salts with acids, 
nor give any precipitate with Mayer's reagent, iodin solution, nor picric 
acid. It is easily removed from an acid solution by immiscible solvents. 

When warmed with potassium hydroxide and chloroform it yields 
phenyl isocyanide, thereby differing markedly from antipyrin and anti- 
phenetidin, though the latter often gives a suggestive odor. 

Its aqueous solution yields a precipitate with bromin water; this 
precipitate is a parabrom acetanilid, which is quite insoluble in water 
and melts 164-156° C. Acetphenetidin does not give any precipitate 
with bromin water. If this test is modified by digesting the acetanilid 
with dilute sulphuric acid 1 in 5, over the steam-bath for two or three 
hours and not allowing the hot acid to become concentrated enough to 
produce charring, the drug will be broken up into its basic substances, 
acetic acid evolved and anilin sulphate remaining in solution. The 
cold dilute solution will give a heavy flocculent precipitate with bromin 
water. Acetphenetidin under similar conditions yields phenetidin sul- 
phate, and a blue color results on adding bromin water. This procedure 
allows for the simultaneous identification of both substances if they occur 
together. 

If desired, the acid aqueous solution obtained by digesting the acet- 
anilid may be treated with excess sodium hydroxide and liberated anilin 
shaken out with ether. 

On boiling 0.1 gram of acetanilid for several minutes with 2 mils of 
hydrochloric acid and adding to the cool solution 3 mils of phenol 1 in 
20 and a saturated solution of calcium hypochlorite, the mixture, which 
will be brownish red, will acquire a blue color with excess of ammonia 
water. 

Acetanilid dissolves without change in concentrated sulphuric acid, 
and remains unchanged if heated at the temperature of the water-bath 
for half an hour. After exposure for four to five hours at this temperature, 



ANILIDES AND PHENETIDINS 835 

it is converted mostly to sulphanilic acid with a small amount of acet- 
sulphanilic acid. Acetphenetidin when heated for an hour or two with 
concentrated sulphuric acid at the temperature of the water-bath yields 
phenetidin sulphonic acid. If a little water is present there is an evolution 
of ethyl acetate and para-amidophenol is formed which is subsequently 
changed to the sulphonate. 

Watson 1 found that when acetanilid was mixed with boric acid in 
a porcelain dish and heated on a free flame an odor suggestive of sweet 
clover or arbutus was evolved and a yellow residue remained. Acet- 
phenetidin left a yellow residue, bat the odor was different and antipyrin 
gave a naphthalene odor and a pink residue. In the case of mixtures the 
odor was increased by adding a drop of water to the residue. 

As acetanilid is removable from acid solutions by means of immiscible 
solvents it will appear in the general scheme of shake-out analysis in all 
the fractions obtained by shaking out the acid mixture. It will, of course, 
appear in greatest amounts in the ether and chloroform fractions, but 
small quantities are removed by petroleum ether. If the acetanilid is 
unaccompanied by any other substance removable from acid solution 
by immiscible solvents, its identification is easy, for it can be recrystallized 
from water and its melting-point and other characteristic properties 
determined. The carbylamine test should be first applied and if negative 
no further concern is necessary. 

Caffein if present may be separated without difficulty by dissolving 
the residue in dilute hydrochloric acid and then throwing out the caffein 
with iodin. The acetanilid remains dissolved, and after the precipita- 
tion is complete, and filtration has been accomplished, it may be recovered 
from the filtrate by destroying the excess of iodin with sulphite, and then 
shaking out with chloroform. If it is desired to identify the caffein it 
is recovered from the iodin precipitate by solution in sulphite solution, 
and shaking out with chloroform from an ammoniacal mixture. 

The presence of antipyrin is indicated by treating with Mayer's 
reagent a portion of an aqueous solution of a suspected mixture, obtained 
by shaking out an acid solution with immiscible solvent. If a well-defined 
precipitate is obtained with this reagent and subsequent tests with picric 
acid and nitric solution give the characteristic antipyrin reactions, a 
separation of the acetanilid may be effected by dissolving the residue in 
hot water allowing enough to hold up the acetanilid when cool, and pre- 
cipitating the antipyrin with picric acid. On filtering the acetanilid can 
be recovered from the filtrate unchanged by shaking with chloroform and 
any picric acid carried along by the solvent is removable by shaking with 
dilute alkali. On evaporating the chloroform the acetanilid will be found 
in the residue and should be crystallized and examined for identification. 

^m. J. Pharm., 1911, 83, 269. 



836 ORGANIC SUBSTANCES 

If it should happen that caffein were present simultaneously with the anti- 
pyrin and acetanilid, the same procedure for separating the antipyrin 
can be employed and the chloroform residue, containing the caffein and 
acetanilid, is treated exactly as described in the preceding paragraph. 
Antipyrin, and acetanilid in admixture cannot be satisfactorily separa- 
rated by crystallization, and when mixed the melting-point is depressed 
some 40-50°. In connection with a mixture containing antipyrin, the 
picrate ought to be separated, washed, and its melting-point determined, 
especially if the sample under investigation is to form the basis of litiga- 
tion. 

If the presence of acetanilid is indicated by the carbylamine reaction 
and caffein is absent, the presence of a phenetidin may be shown by treat- 
ing the residue with dilute sulphuric acid 1 in 5, transferring to a small 
Erlenmeyer and heating over the water-bath for an hour or two, noting 
the odor evolved, and in cases of extreme importance collecting the vapors 
after running them through a condenser and testing them for acetic and 
formic acid. The acid solution in the flask is then diluted and treated 
with bromide-bromate reagent which will give a blue color if a phenetidin 
were present, and a simultaneous precipitate of anilin tribromide if 
acetanilid. It is doubtful if one will meet the three common antipyretics 
combined in one preparation and the employment of acet phenetidin 
and acetanilid together is rare, but in case one encounters a mixture 
where the preHminary tests with the residues indicates all of them a pro- 
cedure along the following lines will enable the worker to draw the proper 
conclusion. The residue should be treated with dilute sulphuric acid 1 in 5 
and heated on the steam-bath as described above, collecting the vapors 
and testing the distillate for formic, acetic, and other acids. The acid 
solution is then diluted with water and shaken out with chloroform, which 
will remove the antipyrin and caffein, and leave the phenetidin and 
anilin sulphates behind. The antipyrin and caffein can then be sepa- 
rated by picric acid and their identities established. The acid solution 
is then warmed to drive off any adhering chloroform, and on cooling is 
treated with iodin solution, which will precipitate the phenetidin in the 
form of an iodin compound. On filtering, the anilin is recovered from 
the filtrate by removing the excess of iodin with sulphite, adding excess 
of alkali and shaking out with ether. 

The treatment of acet phenetidin with acid under the conditions 
above described affects only the radicle attached to the NH group. This 
fact should be borne in mind when drawing conclusions as to identity. 
If acetic acid is evolved and the residual solution gives the characteristic 
reactions, it is practically certain that acetphenetidin is present. If 
desired the residual solution can be acetylated with acetic anhydride and 
the original phenetidin reproduced. 



ANILIDES AND PHENETIDINS 837 

For the evolution of methods for the determination of acetanilid in 
its various mixtures and the simultaneous determination of the accompany- 
ing ingredients we are indebted to W. O. Emery. His procedures are 
based on extended researches covering a period of many years, and the 
details have been perfected from the results of an elaborate system of 
cooperative work. The methods have appeared in the proceedings of 
the Association of Official Agricultural Chemists beginning in 1908 and 
they have been collected and published as a unit for the first time in this 
work. Acknowledgment and full credit is given him herewith. 

SEPARATION OF CAFFEIN, ACETANILID AND SODIUM BICARBONATE 

Caffein 

Weigh out about 3 grams headache powder on a small (5.5-cm.) tared 
filter, 1 wash with successive portions of' chloroform to the amount of 
about 30 mils, collecting the solvent in a 100-mil Erlenmeyer. Distill 
off chloroform by means of a small flame until only a few mils remain. 
Add 10 mils dilute sulphuric acid, and then continue the distillation till 
all the chloroform has gone over, disconnect from condenser, heat gently, 
first on wire gauze to complete solution, 2 finally on steam- or hot-water 
bath until contents of flask have evaporated to about 3 to 4 mils. Cool, 
transfer by washing with water to a separatoiy funnel so that the final 
volume does not greatly exceed 20 mils. Add four times the volume, or 
about 80 mils of chloroform, shake for some time vigorously, allow to 
stand until the chloroform clears perfectly, pass through a small drjr 
filter into a dry 100-mil Erlenmeyer, distill off the solvent and use dis- 
tillate for a second extraction, observing the same method of shaking, 
clearing and filtering as above noted. Distill off chloroform to a small 
volume, transfer residue to a small tared beaker or crystallizing dish by 
means of a few mils of chloroform. Allow to evaporate spontaneously 
or if desired on a steam- or hot-water-bath to dryness, in the latter case 
partially covering the dish toward end of operation with a watch-glass 
in order to avoid possible loss from " popping.' Cool in desiccator and 
weigh as caffein, dry alkaloid. 3 

1 In cases of powder mixtures or tablets containing ground celery seed, much coloring 
matter, cinchona alkaloids, laxative or extractive principles other than acetanilid or 
phenacetin, it is our practice to shake out the latter from dilute sulphuric acid solution 
or suspension by means of chloroform. 

2 In case the preparation contains ground celery seed or certain oily principles it 
sometimes happens that the acid solution does not become entirely clear at this point. 

3 Should the caffein not be colorless or nearly so, the residue is dissolved in about 
10 mils of water, filtered if necessary (in case oily matters are present) through a wet 
filter, and filtrate acidified with dilute hydrochloric acid, the caffein precipitated with 



838 ORGANIC SUBSTANCES 



Acetanilid 



First Method. — The acid solution remaining in separator and contain- 
ing anilin sulphate is run into a 100-mil Erlenmeyer, the filter through 
which the chloroform passed is washed once with a little water, allowing 
latter to run into the separator. Rinse the latter thoroughly, adding the 
aqueous rinsings to acid solutions Now run in slowly and with constant 
agitation a standard solution of potassium bromide-bromate 1 to a faint 
but distinct yellow coloration. The number of mils employed, multi- 
plied by the value of 1 mil in terms of acetanilid, will give the amount 
of acetanilid present. 

Second Method. — The acid solution aforesaid is treated with successive 
small portions of sodium bicarbonate until an excess of this reagent is 
observed in the bottom of separator. Add 50 mils chloroform and 15 to 
20 drops of acetic anhydride, shake for some time vigorously, allow chloro- 
form to clear then pass through the same filter used for the caffein into 
a 100-mil Erlenmeyer, and distill off most of the chloroform. Use this 
distillate for a second shake out, clear, filter, and distill down to a small 
volume, transferring residue and subsequent chloroform washings to a 
tared beaker or dish precisely as in the case of caffein. Allow solvent 
to evaporate spontaneously or by means of a blast or fan, avoiding, how- 
ever, undue heat. 2 Dry in desiccator over quicklime to constant weight. 

Verify final weight by means of titration with standard potassium 
bromide-bromate solution as in the first method. Heat residue with 10 
mils dilute sulphuric acid a half-hour on steam- or vapor-bath, cool, add 
5 mils water and titrate as directed above. 

Sodium Bicarbonate 

The residue left after first treatment with chloroform is weighed when 
dry and represents very nearly the amount of sodium bicarbonate present. 
It may be more accurately estimated by titrating with N/10 sulphuric 

15 to 20 mils of Wagner's reagent, allowed to stand a half hour, filtered and the pre- 
cipitate washed with a few mils of same reagent, the filter together with precipitate 
transferred to separator, decolorized -by means of sodium sulphite and the caffein finally 
extracted with chloroform. 

1 For this purpose the solution is prepared by adding bromin in slight excess to a 
concentrated aqueous solution of 50 mils caustic potash, the liquid diluted till the sepa- 
rated salts redissolve, boiled to expel any excess of bromin and finally made up to one 
liter. This solution is standardized with weighed amounts of acetanilid, or it may 
be so adjusted by further dilution so that 1 mil is exactly equivalent to 1 centigram, 
of acetanilid. For purposes of titration 1 to 2 decigrams are heated a half hour on the 
steam- or water-bath with 10 mils dilute sulphuric acid. 

2 Acetanilid suffers appreciable loss when heated above 40°. 



ANILIDES AND PHENETIDINS 839 

acid, using congo red as indicator, or it may be ignited with dilute sul- 
phuric acid and weighed as sodium sulphate. 
Calculate results on parts per 100. 

CAFFEIN, ANTIPYRIN, AND ACETANILID 

A gross separation of these agents from other materials can usually 
be effected by a procedure similar to that applied to the more simple 
caffein-acetanilid mixtures. Owing to the veiy high solubility, how- 
ever, of antipyrin in aqueous media, a complete extraction therefrom 
by means of chloroform involves a more protracted treatment with this 
solvent than is required in the case of caffein. The separation of both 
caffein and antipyrin from acetanilid is based upon the solubility of 
the former substances and the insolubility of anilin sulphate, into which 
the acetanilid must first be converted, in chloroform. Caffein and anti- 
pyrin are separated one from the other by virtue of their behavior 
toward mercuric nitrate, the antipyrin yielding under the conditions 
of the experiment a molecular compound with the mercury salt, practically 
insoluble in the medium in which the precipitation is effected. After 
filtration, chloroform extracts from an aliquot of the clear filtrate the 
caffein, which is weighed directly, while the antipyrin is estimated, 
after regeneration and recovery from its molecular combination with mer- 
curic nitrate, by titration with standard alcoholic iodin. 



Caffein 

Dissolve an amount of antipyrin-caffein mixture containing not more 
than 1 gram of the former substance in a 200-mil glass-stoppered flask 
in about 150 mils saturated aqueous solution of potassium nitrate, heat 
on the steam-bath nearly to the boiling temperature, then treat, a few 
drops at a time, with a solution of mercuric nitrate (prepared by dissolving 
25 parts red oxide of mercuiy in 60 parts of 25 per cent nitric acid by means 
of gentle heat, diluting with water to 200 mils then saturating this solu- 
tion with potassium nitrate), the flask being agitated after each addition 
in order to clarify the liquid; 10 to 12 mils reagent should suffice to effect 
complete precipitation. Any undue excess of mercuric nitrate is to be 
avoided. On standing several hours or until the product has acquired 
the temperature of the room fill flask to mark with saturated solution of 
potassium nitrate, mix thoroughly, then filter by the aid of suction, using 
in this connection if available, a small (4-cm.) perforated plate and the 
requisite filter. Transfer an aliquot (100 mils) of the filtrate to a sepa- 
ratory funnel and extract five times with 50-mil portions of chloroform, 
the solvent from each extraction being run through a small pledget of 



840 ORGANIC SUBSTANCES 






cotton and dry filter into a 200-mil Erlenmeyer. On completion of the 
third extraction, distill the chloroform down to about 40 mils, using the 
distillate thus obtained for the two final extractions. Add the chloro- 
form from the fourth extraction to that remaining from the first three, 
transfer the whole to a second separator and shake vigorously with 5 
mils water, in order to remove traces of potassium nitrate. Run the 
chloroform through cotton and filter into a second Erlenmeyer, to which 
is added the solvent, from the fifth or final extraction, after this has been 
subjected to washing in the second separator above mentioned. Distill 
the chloroform from the combined extractions down to a small volume, 
transfer residue to a small tared beaker, evaporate at the ordinary temper- 
ature or at a moderate heat on the vapor-bath, and weigh the residual 
caffein. If the various manipulations have been conscientiously carried 
out, it will be found that the product is veiy nearly pure. In any case 
it should be dissolved in water, a few drops of HC1 added and the liquid 
saturated with H2S. Should any quantity of the ant ipyrin-merc uric 
nitrate compound have been taken up by the chloroform, a faint color- 
ation or even slight precipitate will result, which may be filtered off in 
a Gooch, dried and weighed. From the formula: C11H12N2O • Hg(NOs)2, 
it will be seen that 1 part of HgS would correspond to 2.21 parts of the 
molecular compound, hence the quantity of the latter, calculated from 
the amount of mercuric sulphide obtained, subtracted from the crude 
caffein would yield one-half the true amount of caffein present in the 
original mixture. 

Antipyrin 

The amount of this substance can be determined by difference provided 
the combined weight of both caffein and antipyrin is known, otherwise 
the estimation may be carried out as follows : 

Weigh out on a small (5.5 cm.) filter an amount of the powdered sample 
equal to or a multiple of the average weight of one tablet, wash with suc- 
cessive small portions of 95 per cent alcohol, in quantity about 20 to 30 
mils sufficient at least to extract all the antipyrin present in the mixture. 
Collect solvent in a 100-mil Erlenmeyer, add 10 mils of an alcoholic solu- 
tion of mercuric chloride (5 grams in 100 mils 95 per cent alcohol), then 
run in a standard solution of pure iodin (1.351 grams resublimed iodin 
dissolved in 100 mils 95 per cent alcohol, 1 mil of which is either exactly 
or approximately equivalent to 10 mg. pure antipyrin until a faint yellow T 
coloration persists. The number of mils required to bring about this 
result, multiplied by the value of 1-mil in terms of antipyrin will give 
the quantity of this substance present in the sample under examination. 

Comments and Suggestions. — If desired the antipyrin can be readily 
recovered from its compound with mercuric nitrate. To this end collect 



ANILIDES AND PHENETIDINS 841 

all the precipitate on the porous plate by the aid of saturated saltpeter 
solution, remove to beaker, add 50 mils water, acidify with HC1, then 
saturate first in the cold, finally in the heat with H2S, filter and wash 
the HgS thoroughly with hot water, collecting filtrate in a porcelain 
evaporating dish. Neutralize the free acid with ammonia and evaporate 
on a steam-bath to about 10 mils. Transfer to a separatory funnel by 
the aid of water so that the final volume does not exceed 20 mils. Extract 
five times with 50-mil portions of chloroform, drying, and collecting the 
solvent in the usual way in an Erlenmeyer. Distill off most of the chloro- 
form, transfer residue to a tared beaker by means of additional solvent, 
evaporate on a steam-bath to apparent dryness, cool, and weigh. Dis- 
solve the antipyrin thus obtained in 95 per cent alcohol, and titrate all 
or an aliquot with standard alcoholic iodin. 

ACETANILID AND QUININ SULPHATE 

The separation of these two substances is based on the fact that the 
bisulphate of quinin in aqueous-acid solution is practically insoluble in 
U. S. P. chloroform, while acetanilid under the same conditions is readily 
taken up by this solvent. The procedure, therefore, resolves itself into 
the following steps : 

Ascertain the weight of 20 or more tablets, reduce to a powder and 
transfer to a glass-stoppered or well-corked flask. Weigh out on a metal 
scoop, watch-glass, or other convenient object an amount of powdered 
sample equal to or a multiple of the average weight of one tablet, trans- 
fer to a separatory funnel (Squibb form), add 50 mils chloroform, 20 mils 
water and 10 drops dilute sulphuric acid, sufficient at least to insure a 
slight excess of this reagent in the mixture. Shake for some time vigor- 
ously, allow to clear, then draw off the solvent through a small pledget 
of cotton and a small (5.5 cm.) dry filter into a 200-mil Erlenmeyer. 
Repeat extraction twice, using the same amount of chloroform as in the 
first operation. Use a fresh pledget of cotton for each withdrawal of 
solvent, putting the moist cotton after passage of the chloroform into 
the filter, where with the latter it is allowed to dry spontaneously, or by 
placing a few moments on the cover of a steam-bath. On completion 
of the third extraction the separation of the two ingredients in question 
is practically complete, all the acetanilid being in the chloroform, while 
the quinin remains in the aqueous-acid solution, with traces also in both 
cotton and filter. 

Acetanilid 

Distill the chloroform from the three extractions by the aid of gentle 
heat down to about 10 mils, add 10 mils dilute sulphuric acid (1 : 10 by 



842 ORGANIC SUBSTANCES 

volume), continuing the distillation until all the solvent has passed over. 
Remove to a steam- or vapor-bath and digest for about one hour or until 
the liquid has evaporated to about two-thirds the original volume. Add 
20 mils water, digest thirty minutes longer, add 10 mils cone. HC1, then 
titrate with a standard solution of potassium-bromide-bromate, sub- 
stantially as outlined in the method for the estimation of acetaniiid and 
caffein. 

Quinin Sulphate 

Wash filter and cotton used in drying the chloroformic solution of 
acetaniiid once with 5 mils water, allowing latter to run into the aqueous- 
acid solution of quinin. Add solid sodium bicarbonate (or aqueous 
ammonia) in slight excess, then extract with three 50-mil portions of 
chloroform, washing each portion in rotation with 5 mils water, and passing 
the solvent after clearing through cotton and a dry filter, exactly as in 
the extraction of acetaniiid. Distill the chloroform from the several 
extractions down to about 10 mils then, if it seems desirable to weigh the 
quinin as such, transfer residue to a small tared beaker by pouring and 
subsequent washing with chloroform, evaporate to apparent dryness on 
the steam-bath, heat for an hour at 125° in an air-bath, cool, and weigh. 
If, as is usually the case in combinations like the one at present under 
examination, the weight of quinin sulphate is desired, distill the chloro- 
formic solution of quinin to apparent dryness by means of gentle heat, 
dissolve residue in 3 to 5 mils neutral alcohol (just sufficient to prevent 
precipitation by the standard acid) and titrate with N/50 sulphuric acid 
(using two drops methyl-red solution as indicator) till color changes to 
faint red. Remove to steam-bath and heat until most of the alcohol has 
been expelled, the color of the liquid having in the meantime become 
^^ellow again. Now add sufficient acid to restore the faint red coloration, 
note number of mils expended, then multiply same by 8.66 the value of 
1 mil N/50 sulphuric acid in mgs. of quinin sulphate (C2oH24N202)2 • 
H2SO4 • 7H2O, to get the weight of this substance in sample taken. In 
the event that the quinin as such has first been weighed, the weight should 
be further checked by titration, substantially as outlined above. 

Comments and Suggestions. — The composition of many medicinal 
preparations in pill or tablet form is frequently of such a natuie as to com- 
pletely inhibit any rational separation of the active organic constituents by 
means of immiscible solvents in the ordinary separatory funnel, owing 
to the formation of persistent emulsions even on cautious agitation. To 
obviate this difficulty various flattened types of separators have been 
suggested one of which illustrated on page 25, yields gratifying results, 
a twenty-minute treatment on the rotating table suffices to effect a maxi- 
mum distribution of the substances involved. Wherever available such 



ANILIDES AND PHENETIDINS 843 

separators will be found highly advantageous in obviating the delay and 
annoyance occasioned by emulsifying mixtures. 

Since quinin sulphate readily loses a portion of its water of crystalliz- 
ation when exposed to dry air, the amount of sulphate found, whether 
calculated from quinin as weighed or from that determined volumetrically, 
need not necessarily correspond with the declared amount of this com- 
modity indicated on the sample under investigation. 

ACETANILID, QUININ SULPHATE AND MORPHIN SULPHATE 

As in a mixture of acetanilid and quinin sulphate, so likewise in the 
present combination, the alkaloidal constituents in aqueous-acid solu- 
tion are separated from the third by virture of the insolubility of their 
sulphates in chloroform. The separation of the alkaloids themselves is 
based on the ability of morphin to yield with an alkaline base a morphinate 
insoluble in chloroform. The procedure thus resolves itself into the follow- 
ing particulars. 

Acetanilid 

Transfer to a separatory funnel an amount of the powdered sample 
equal to or a multiple of the average weight of one tablet (the amount 
of morphin sulphate represented should not be less than J grain), add 20 
mils water and 10 drops dilute sulphuric acid, then extract with three 
50-mil portions alcohol-free chloroform, the subsequent manipulations 
being substantially as directed for this ingredient in the combination: 
Acetanilid and Quinin Sulphate. 

Quinin Sulphate 

Wash filter and cotton used in drying the chloroformic solution of 
acetanilid once with 5 mils water, uniting latter with the aqueous-acid 
solution and quinin and morphin. To this solution add 4 to 5 mils aqueous 
sodium hydroxide (5 grams pure NaOH in 50 mils water), then extract 
with three 50-mil and one 25-mil portions U. S. P. chloroform, transferring 
latter in rotation to a second separator (Squibb type) containing 5 mils 
water, wash, and pass the nearly clear chloroform through a pledget of 
cotton and small filter into a 200-mil Erlenmeyer, from which the solvent 
is later removed by gentle distillation and the residue titrated, sub- 
stantially as outlined for quinin in the combination: Acetanilid and 
Quinin Sulphate. 

Morphin Sulphate 

Wash filter and cotton empk^ed in the preceding operation with 
5 mils water, which latter together with that portion used to wash the 



844 ORGANIC SUBSTANCES 

chloroformic solution of quinin is united with the aqueous-alkaline solu- 
tion of sodium morphinate. Now add 0.5 gram ammonium chloride 
(an amount slightly in excess of that required to free the morphin as well 
as convert the NaOH into NaCl) and to the resulting ammoniacal solution, 
add 45 mils U. S. P. chloroform and 5 mils alcohol, then extract and draw 
off solvent into a second separator containing 5 mils water, wash, allow 
to clear, then pass chloroform through cotton and filter into a 200-mil 
Erlenmeyer. Repeat extraction and subsequent washing with one 50- 
mil, one 40-mil, and one 30-mil, U. S. P. chloroform, finally collecting 
the solvent from all extractions and distilling from the aforesaid Erlen- 
meyer down to about 10 mils. Transfer by pouring and washing with 
additional chloroform to a small tared beaker, evaporate on the steam- 
bath to dryness, cool, and weigh the residual morphin now appearing as 
a transparent varnish. To render crystalline, dissolve by warming with 
1 mil neutral alcohol, add about the same quantity of water drop by drop, 
rubbing the glass with a rod to induce crystallization, then evaporate 
slowly on the steam-bath to dryness. Cool and weigh a second time. 
Check the weight of morphin thus found by titration with N/50 sulphuric 
acid, using a drop of methyl-red solution as indicator. To this end dis- 
solve the morphin in 1 to 2 mils warm neutral alcohol, then after solu- 
tion is complete add the acid till color changes to faint red. Evaporate 
most of the alcohol on the steam-bath, and in the event that the color 
has reverted to yellow add just sufficient acid to restore the faint red 
coloration. Note volume of acid expended, then multiply the number 
of mils by 7.53 (the number of mg. morphin sulphate equivalent to 1 mil 
N/50 sulphuric acid) to ascertain the quantity of morphin sulphate in the 
sample taken. The amount of anhydrous or of crystallized alkaloid can 
also be determined from the titration value by use of the proper factor. 

Comments and Suggestions. — For the purpose in question alcohol- 
free chloroform may be conveniently prepared by washing the pharma- 
copeal product several times with water. 

All cotton used for drying chloroform should first be freed from fatty 
material or other extractives by thorough washing with this solvent, all 
of which latter may be regained by distillation. 

In the various operations involving fixation and subsequent liberation 
of morphin by means of fixed alkali and ammonium chloride, strict atten- 
tion should be paid to the matter of adding these reagents, since any undue 
excess of either might nullify the entire procedure. Any large excess of 
NaOH would naturally require for its reduction a correspondingly large 
amount of NH4CI, the latter in turn yielding its pro rata of NEUOH, 
relative large quantities of which through interaction with NaCl tend 
to inhibit any permanent liberation of the alkaloid and thus prevent a 
complete extraction. Furthermore, the presence of relatively large quan- 



ANILIDES AND PHENETIDINS 845 

tities of NH4OH as such operates to a partial retention of morphin in solu- 
tion, due in part, possibly, to the formation of the hydrochloride of this 
alkaloid. 

In spite of all precautions in the matter of excluding impurities from 
morphin, the amount of this substance as found by weight will usually 
be greater than that determined volumetrically. In order to insure 
greater accuracy in volumetric operations with alkaloidal substances as 
quinin, morphin, etc., the suggestion is made, in all cases where possible, 
that the strength of the standard acid used be checked by titration against 
the pure alkaloid under examination. 

ANALYSIS OF MIXTURES CONTAINING CODEIN, ACETANILID, AND 
SODIUM SALICYLATE 

The separation and estimation of these three substances is effected 
in the following manner: Reduce 20 tablets to a fine powder, then weigh 
out an amount equal to the average weight of one tablet, transfer to a 
separatory funnel, add 50 mils chloroform, 10 mils of water, and about 
1 mil of dilute sulphuric acid, sufficient to insure acidity in the solution. 
Shake vigorously, allow to clear, then draw off solvent through a pledget 
of cotton and dry filter into a second separatory funnel of about 200 to 
250-mil capacity. Extract a second and third time, using the same amount 
of chloroform as before. After each withdrawal of the solvent throw the 
cotton pledget into the separator and substitute a fresh one in its place. 
Treat the combined chlcroformic extracts as directed under acetanilid. 

Codein 

Wash the filter used to dry the chloroform solution of acetanilid and 
salicylic acid with 5 mils of water, receiving latter in the separator con- 
taining the aqueous acid solution of codein. Add solid sodium bicar- 
bonate in slight excess, then extract by means of vigorous shaking with 
three 50-mil portions of chloroform. Dry the solvent with cotton and 
filter as above, collect in 200-mil Erlenmeyer, then distill the liquid by 
the aid of gentle heat down to about 10 mils. Transfer the residue by 
pouring and rinsing with fresh chloroform, to a small tared beaker, evapo- 
rate to apparent dryness on the steam-bath, cool, and weigh as anhydrous 
codein. Verify by moistening the residue with a little neutral alcohol 
and titrating with N/50 sulphuric acid, using methyl red (1 drop alcohol 
soluble) as indicator. 

Acetanilid 

To the chloroform solution of acetanilid and salicylic acid add 20 
mils of water, and for every 100 mg. of salicylic acid known or believed to 



846 ORGANIC SUBSTANCES 

be present, 1 gram of anhydrous sodium carbonate. Shake vigorously, 
allow to clear, withdraw the chloroform through cotton, and filter into 
a 200-mil Erlenmeyer. Extract the aqueous-alkaline solution with two 
10-mil portions of chloroform in order to remove traces of acetaniiid 
taken up temporarily by the water. Distill the united chloroformic 
extracts by the aid of gentle heat down to about 10 mils. Introduce into 
flask 10 mils of dilute sulphuric acid (1 : 10 by volume) and digest on the 
steam-bath until the residue amounts to 3 to 5 mils then add 20 mils of 
water and 10 mils of concentrated hydrochloric acid. Into this solution 
run slowly a standard solution of potassium bromide-bromate until a dis- 
tinct yellow coloration persists. Multiply the number of mils required 
to complete the formation of tribromanilin by the value of 1 mil in terms 
of acetaniiid to ascertain the amount of this substance originally present 
in the sample taken. 

Sodium Salicylate 

Transfer the aqueous soda solution containing the salicylic acid from 
the separator to a 200-mil Erlenmeyer, dilute with water to about 
100 mils, heat nearly to boiling, then run in from a burette 25 to 
50 mils of N/5 iodin in potassium iodide (or double this quantity of 
N/10 strength) sufficient to insure an excess of this reagent. Digest 
the product on the steam-bath for one hour, adding iodin solution from 
time to time in order to maintain a slight excess. The reddish, insoluble 
precipitate has the composition (CgH 2 120)2, being identical with the " red 
substance " first described by Lautemahn : and later used by Bougault 2 
in the separation of salicylic from benzoic and cinnamic acids. Remove 
any excess of iodin by the addition of a few drops of sodium thiosulphate 
solution, decant liquid through a tared Gooch, care being taken that 
most of the precipitate remains in the flask. Add 50 mils of boiling water 
to the latter, digest ten minutes on steam-bath, then pour into Gooch, 
into which all the reddish precipitate is gradually washed, using for this 
purpose and subsequent washings about 200 mils of hot water. Dry in 
air-bath to constant weight. The weight of precipitate multiplied by 
0.4658 will give the amount of sodium salicylate originally present in the 
sample. 

Should acetphenetidin instead of acetaniiid be employed in the above 
combination, the procedure need be modified only to this extent, that the 
chloroform solution of acetphenetidin and salicylic acid, after elimination 
of the latter substance through treatment with sodium carbonate, is dis- 
tilled down to about 10 mils and the residue transferred to a small crys- 

1 Liebig's Annalen, 1861, 120: 309. 

2 J. Pharm. Chim., 1908, 28, 145. 



ANILIDES AND PHENETIDINS 847 

tallizing dish for final evaporation .of solvent and weight of resulting 
acetphenetidin. 

In this connection it may not be amiss to state that the quantitative 
separation of codein, acetanilid, and sodium salicylate could be effected 
in substantially the following manner: To the mixture in separatory 
funnel add about 100 mg. of sodium bicarbonate, 10 mils of water and 
50 mils of chloroform. Extract three times with this quantity of solvent. 
The sodium salicylate remaining in the separator is transferred to an 
Erlenmeyer and treated with iodin solution as above directed, after the 
extraction of codein and acetanilid is accomplished by shaking out the 
chloroform solution of these two substances with 10 mils of dilute sul- 
phuric acid. The acid solution is w r ashed twice thoroughly with about 
10 mils of chloroform in order to remove traces of acetanilid taken up 
temporarily by the aqueous medium. The latter substance, after removal 
of solvent and subsequent hydrolysis, is titrated with standard bromide- 
bromate solution, as already described. The aqueous-acid solution of 
codein is treated with solid sodium bicarbonate in excess, the alkaloid 
thereupon extracted with chloroform. On removal of solvent by distil- 
lation and evaporation the codein is first weighed and then titrated with 
N/50 sulphuric acid. 

ESTIMATION OF CAFFEIN, ACETANILID, QUININ, AND MORPHIN 

Weigh out an amount of the powdered sample containing at least 
one-fifth grain (about 12 mg.) of morphin, transfer to a separatory funnel, 
adding 20 mils of water, 10 drops of dilute sulphuric acid, and 60 mils 
of alcohol-free chloroform. Shake vigorously, allow to clear, then draw 
off through a pledget of cotton and small diy filter into a second separator, 
in which the solvent is washed with 5 mils water to remove any alkaloidal 
traces that may have been taken up by the chloroform. The latter is 
finally passed through a small filter into a 200-mil Erlenmeyer for sub- 
sequent distillation and treatment in the separation of caffein and acet- 
anilid. 

Quinin 

Repeat the extraction of the aqueous-acid mixture with 50, 40, and 
30-mil portions of chloroform, each portion of solvent being treated as 
directed for the first. The wash water is returned to the first separator, 
the liquid rendered alkaline by the addition of strong caustic soda in slight 
excess. We now have the morphin as sodium morphinate insoluble in 
chloroform, while the quinin is precipitated as a white flocculent mass. 
Shake out four times with 60-, 50-, 40- and 30-mil portions of alcohol- 
free chloroform, the solvent from each operation being passed through 



848 ORGANIC SUBSTANCES 

cotton and a dry filter, prior to reception in the Erlenmeyer and distillation 
from the quinin dissolved therein. Transfer to a small tared beaker by 
pouring and rinsing with a small quantity of chloroform, evaporate to 
apparent dryness on the steam-bath, heat amorphous residue one hour 
at 125° C. in an air-bath, cool, and weigh. Dissolve in alcohol, transfer 
to a graduated 100-mil flask, fill to mark with water and sufficient alcohol 
to prevent precipitation of alkaloid; then remove with a pipette an aliquot 
containing at least one-tenth of the total amount of quinin present and 
titrate with N/50 sulphuric acid, using as indicator 1 to 2 drops of methyl 
red (100 mg. dissolved in 100 mils of alcohol). The number of mils 
required multiplied by 8.66 will give the number of milligrams of quinin 
sulphate in the aliquot titrated. 

Morphin 

In order to recover the morphin from its combination with sodium, 
add an amount of ammonium chloride slightly in excess of that required 
to react with the caustic soda previously introduced into the separator and 
as much common salt as the liquid will dissolve. A slight excess of the 
latter substance above that necessary to saturate the mixture can do no 
particular harm other than render the subsequent removal of the chloro- 
form less quantitative. Extract four times by means of vigorous shaking 
with 50-, 45-, 40-, and 30-mil portions of Pharmacopoeial chloroform, to 
the first portion of which are added 5 mils of alcohol prior to extraction. 
Wash each portion of solvent in a second separator with about 5 mils of 
water, after extraction but before passing through cotton and filter into 
a 200-mil Erlenmeyer for distillation. Distill off most of the solvent, 
transfer residue by pouring and rinsing with fresh chloroform to a tared 
crystallizing dish, evaporate to apparent dryness on the steam-bath, treat 
residue with a few drops dilute alcohol should it seem desirable to obtain 
the morphin in crystalline form, heat again to dryness, cool and weigh. 
Verify by dissolving the alkaloid in a few mils of warm alcohol and titrating 
with N/50 sulphuric acid, using as indicator a drop of methyl red solu- 
tion. The number of mils required multiplied by 7.53 will give the number 
of milligrams of morphin sulphate present in the original sample. 

Caffein 

Distill the chloroformic solution of caffein and acetanilid down to 
about 10 mils, add 10 mils of dilute sulphuric acid (1 : 10), digest on steam- 
bath until contents of flask have evaporated to about 5 mils, add 10 mils 
of water and evapora + e a second time; transfer residue to a separator by 
pouring and rinsing with water so that the final volume does not exceed 
20 mils, then make three extractions with 50-mil portions of chloroform. 



ANILIDES AND PHENETIDINS 849 

After clearing, pass solvent through cotton and dry filter into a 200-mil 
Erlenmeyer; distill from the combined extractions down to about 10 mils 
then transfer to a small tared crystallizing dish by pouring and careful 
rinsing with small quantities of fresh chloroform. Allow to evaporate 
spontaneously, or at a moderate heat, on a vapor-bath to apparent dry- 
ness. Remove from heat immediately on the appearance of a crystalline 
residue. Cool in a desiccator and weigh as anhydrous caffein. 

Acetanilid 

Draw off the acid solution remaining in separator into the same Erlen- 
meyer previously used in effecting the hydrolysis, wash out separator 
several times with water to insure complete removal of former contents; 
heat the aqueous-acid solution a short time on steam-bath to expel all 
traces of chloroform; wash the filter used in the preceding operation to 
dry the chloroform solution of caffein at once with 5 mils of water, receiving 
latter in the main solution of anilin sulphate; add 10 mils of concentrated 
hydrochloric acid, and titrate with a standard potassium bromide-bromate, 
1 mil of which is equivalent to 10 mg. of pure acetanilid. The number of 
mils required to complete the precipitation, multiplied by the value of 
1 mil in terms of acetanilid, will give the quantity of this substance 
originally present in the sample taken. In the event that the quantity 
of acetanilid present in the tablet is relatively large, as is frequently 
the case w r hen compared with the morphin content, it is best to titrate 
only an aliquot of the anilin sulphate solution. 

METHOD FOR ANALYZING LIQUID HEADACHE MIXTURES. EMERY 1 

Alcohol 

Cool sample to 25° C, at which temperature fill a 25-mil flask to mark, 
weigh, then transfer to a distilling apparatus, rinsing out the flask several 
times with water, employing for this purpose a total of 25 mils. Distill 
into a 50-mil flask (surrounded by ice-water) until the liquid in the dis- 
tilling flask is reduced to 10 mils. Transfer the somewhat turbid dis- 
tillate (due to volatile oil) to a separator provided with short delivery 
tube, rinse out the flask several times with a total of 15 mils water, saturate 
the combined solution with sodium chloride, shake vigorously for two 
minutes with 25 mils low boiling (40-60° C.) petroleum ether, then allow 
to stand fifteen minutes. Draw off entire liquid into a second separator, 
washing out the first (which still contains undissolved salt) with 5 mils 
saturated salt solution into the second. Draw off the lower layer into 
first separator, from which the undissolved salt has in the meantime been 
1 U. S. Dept. Agri. Bu. Chem. Bull, 152, p. 256. 



850 ORGANIC SUBSTANCES 

removed, and shake it out as above with a second portion of 25 mils satu- 
rated solution, transferring resultant mixture to the distillation flask. 
Distill into a 50-mil flask (cooled in ice-water) nearly to mark, allow 
temperature to rise to 25° C, fill to mark, and determine the specific 
gravity at this temperature in a Squibb pyknometer, calculating the per 
cent of alcohol by "volume from tables. The percentage obtained multi- 
plied by 2 will give the amount of alcohol in original sample. 

Caffein-Acetanilid 

Transfer residual crystalline magma containing the cafTein, acetanilid, 
and sodium salicylate from distilling flask to a separatory funnel by the 
aid of successive portions of water (ending with a little chloroform if 
necessary to remove all traces of acetanilid) so that the final volume of 
the aqueous solution does not exceed 50 mils. Make five separate extrac- 
tions by means of vigorous shaking, each time with 70 mils chloroform. 
Allow solvent to clear after each extraction, pass through small (5.5-cm.) 
dry filter into a 200-mil Erlenmeyer and distill by the aid of a small flame 
until about 60 mils have gone over. Use this distillate for each subsequent 
extraction, making up to 70 mils as found necessary with fresh solvent. 
After the final extraction and distillation of chloroform, add 10 mils dilute 
sulphuric acid and evaporate to 4 or 5 mils on steam-bath, transfer the 
residual acid solution of cafTein and anilin sulphate to a 100-mil gradu- 
ated flask, fill to mark and determine cafTein and acetanilid in an aliquot 
of 25 mils as directed in method for Estimation of CafTein, Acetanilid, 
and Sodium Bicarbonate. 

Sodium Salicylate (Salicylic Acid) 

The aqueous solution remaining in separatory funnel and containing 
the sodium salicylate and glycerin is rendered acid with hydrochloric 
acid and extracted three separate times by means of vigorous shaking, 
70 mils chloroform being employed for each extraction. The solvent, 
after clearing, is run into a 200-mil Erlenmeyer (containing 10 mils water 
and 1 gram dry sodium carbonate, sufficient to fix all the salicylic acid 
present) and distilled over a small flame until most of the chloroform has 
been expelled. After the final distillation and elimination of all chloro- 
form, transfer the aqueous soda solution of sodium salicylate to a liter 
flask, add 10 grams dry sodium carbonate, fill to mark, pipette an aliquot, 
of 100 mils into a 200-mil Erlenmeyer, heat nearly to boiling, then add 
about 35 mils N/5 iodin in potassium iodide (or double this quantity of 
N/10 iodin solution), enough to ensure an excess of iodin. Heat one 
hour on steam-bath to near the boiling temperature, during which time 
a violet-red precipitate of tetraiodophenylenquinon, (CeEb^O^, will 



ANILDIES AND PHENETIDINS 851 

appear. Remove excess of iodin by the addition of a few drops of hypo 
solution, decant liquid off into a tared Gooch crucible, care being taken 
that most of the precipitate remains in the flask. Add 50 mils boiling 
water to the iodin compound in flask, digest for ten minutes on steam- 
bath, then pour into the Gooch, into which the precipitate is gradually 
washed by means of hot water, using for this purpose about 200 mils. 
Dry to constant weight in air-bath at 100° C. Multiply weight of pre- 
cipitate by 0.4658 and the product will be the weight of sodium salicylate 
in aliquot taken. Report all results in parts per 100. 

Methyl Acetanilid— Exalgin, C 6 H 5 N(CH3)C2H 3 

Methyl acetanilid crystallizes in needles or tablets, melting 100- 
101° C. It is soluble in alcohol and boiling water, but only slightly in 
cold water. When hydrolyzed with acid it gives acetic acid and methyl 
anilin. The latter substance resembles anilin, but is lighter than 
water and boils 192°, and a solution of calcium hypochlorite colors it violet 
and then brown. 

Acetanilid, and exalgin may be distinguished by the following reaction: 
about 0.05 gram is treated with 10 drops of hydrochloric acid and boiled 
for two minutes. The liquid is then cooled, 5 more drops of hydrochloric 
acid are added, then 1 drop of 1 per cent sodium nitrite solution; after 
allowing reaction to take place for ten minutes, 1 mil of phenol is added 
and then gradually enough strong sulphuric acid to give a homogeneous 
mixture. Of this 0.5 mil is treated with sufficient caustic soda solution; 
sp. gr. 1.332, to give a clear solution. In the case of exalgin a blue color 
will be obtained and with acetanilid a yellow tint. Mixtures will naturally 
vary from yellowish to green. The various details of the test must be 
rigorously observed. 

It is used medicinally as an analgesic and antirheumatic. 

Ethylacetanttid, C 6 H 5 N(C 2 H 5 )C 2 H 3 

Ethylacetanilid melts 50° C. 

Iodacetanilid 

Acetparaiodanilid, CeHsNHI^HsO). Iodacetanilid melts 181-182° 
C., soluble in alcohol and glacial acetic acid, insoluble in water. 

Salifebrin 

Salifebrin or " salicylanilid " is the name given to the product obtained 
by the fusion of salicylic acid and acetanilid. 



852 ORGANIC SUBSTANCES 

Formanilid, C 6 H 5 NH(HCO) 

Prepared from anilin and formic acid similarly to formation of acet- 
anilid. It forms colorless crystals, melting 46°, soluble in alcohol, 
water, and glycerin. Its physiological properties are similar to acetanilid, 
and it has many similar chemical properties as would be expected from its 
similarity in composition. On heating with dilute sulphuric acid, formic 
instead of acetic acid is disengaged, thus furnishing important evidence 
as to its identification. 

Gallanilid, Gallanol, C 6 H 5 NHCOC 6 H 2 (OH) 3 +2 H 2 

Gallanol is the anilid of gallic acid. It is a brownish crystalline sub- 
stance, melting 205° C, soluble in alcohol, ether, and boiling water, and 
insoluble in chloroform. It is used as an antiseptic in skin diseases. 
It combines the properties of an anilid and gallic acid and on hydrolysis 
may be split up into its components which are then separable and can be 
identified. 

Benzanilid, Phenylbenzamide, C 6 H 5 NH(COC6H5) 

Benzanilid is a white or reddish-white crystalline substance, melting 
160-162° C, soluble in alcohol, somewhat in ether but only slightly in 
water. It is used as an antipyretic. 

Acettoluides 

The toluides have already been mentioned on page 833. These bodies 
have some value as antipyretics and may be substituted for acetanilid 
in headache mixtures. Their general properties will of course simulate 
those of acetanilid, but they will yield toluidines on hydrolysis with acids. 
The ortho and meta compounds have a melting-point which is in close 
proximity to that of acetanilid. 

Pyoktanins 

Rosaniline base is triamidotolyl diphenyl carbinol. 

/C6H3(CH 3 )NH2 
NH 2 C 6 H4C(OH)< 

X C 6 H4NH 2 

Dyes of this type may be considered as derivatives of triphenyl methane. 
In pararosaniline the amido tolyl group is replaced by the amido phenyl. 
By use of various homologues of anilin many other compounds are pos- 
sible and have been prepared. 



ANILIDES AND PHENETIDINS 853 



Pyoktanin Blue 

This compound consists of the hydrochlorides of penta and hexa- 
methylpararosaniline and is a violet powder. It is soluble in alcohol, 
chloroform, water, and glycerin and insoluble in ether. It is a valuable 
antiseptic and disinfectant and is used in diseases of the mucous membrane 
and especially in veterinary practice, for it has been found to be a valuable 
remedy in the foot and mouth disease. It is dispensed in solution in 
capsules and in pencils, and is sometimes applied combined with mer- 
curic chloride. 

I 

Pyoktanin Yellow 

Pyoktanin yellow or auramine is imino-tetramethyl diaminodiphenyl- 
methane hydrochloride. It is a yellow powder somewhat resembling- 
sulphur and is soluble in alcohol and water. It is employed in skin 
diseases and in ophthalmic practice. 



AMINOPHENOLS AND THEIR DERIVATIVES 

Phenetidins 

When carbolic acid is added to nitric acid sp. gr. 1.11 in the cold a mix- 
ture of ortho and para nitrophenols is formed. The former may be sepa- 
rated by steam distillation, and the latter which is left behind, dissolves 
in hot water from which it separates on cooling. The meta body is pre- 
pared by reducing meta-dinitrobenzol, diazotizing with dilute sulphuric 
and nitrous acid and then boiling, by which process the meta nitrophenol 
is produced. 

On reduction, corresponding amino compounds are obtained. The acid 
character of the phenol is lost in presence of the amino group and the 
products yield salts only with acids, but they may still be esterified on 
the hydroxyl and the hydrogen of the amino group is replaceable by radi- 
cles. 

These esterified bodies are called anisidins or phenetidins, according 
to the radicles present, the methoxy group gives the former, and the ethoxy 
the latter. Then, of course there are the o-,m-, and p-modifications of each. 

The acetylated phenetidins are the substances of this group which 
have received the greatest attention by the medical profession and the 
manufacturing pharmacist. The best known is acetphenetidin or phen- 
acetin. In preparing them the general procedure consists in esterifying 
the hydroxyl group of the nitro phenol before reducing the nitro group, 
and after accomplishing the reduction and separating, the acid radicle 
is introduced into the amino group. 



854 



ORGANIC SUBSTANCES 



A tabulation of the aminophenols and their principal derivatives 
follows: 





Ortho 


Meta 


Para 




M.pt. 


B.pt. 


M.pt. 


B.pt. 


M.pt. 


B.pt. 


•OH 

Aminophenol, C 6 H 4 <f 

^NH 2 


170° 


Sub- 
limes 






184° 




Acetyl deriv., CeH^ 

\NHCOCH 3 


201° 








179° 




Methyl Ester, (Anisidin) 




228° 




251° 


56° 


246° 


Ethyl Ester, (Phenetidin) 


242° 


229° 




180-205° 

at 100 

mm. 




253° 


/OCH3 
Methacetin, CeH^ 

^NHCOCHs 


84° 


204° 




i 


127° 




/OC 2 H 5 
Acetphenetidin, CeH^ 

\NHCOCH3 


70° 






96-70° 




(J& 


/OCoH 5 
Phenocoll, C 6 H/ 

X NHCOCH 2 NH 2 












100.5° 



Para-acetanisidin, Methacetin, CeH^ 



OCH 3 
NHCOCH3 



This a crystalline substance, melting 127°, slightly soluble in cold 
water, ether, and petroleum ether, but dissolves without difficulty in 
boiling water, alcohol, acetone, chloroform, dilute acids, and alkalies. 
When boiled with insufficient water to effect its complete solution, the 
undissolved portion melts, resembling acetanilid in this phenomenon, 
but differing entirely from acetphenetidin. It is used for the same pur- 
poses as its homologue. 

Para-acetphenetidin 

Para-acetphenetidin or phenacetin is the most important substance 
in this group. It is used for the same purposes as is acetanilid and in 
general may be stated to occur in mixtures of the same ingredients. 



ANILIDES AND PHENETIDINS 855 

It is a white crystalline substance, melting 134-136° C, very slightly 
soluble in cold water, and somewhat more in boiling, and readily in alcohol, 
chloroform, and ether. It is removable from an acid mixture slightly by 
petroleum ether and quite completely by ether. Cold dilute sulphuric 
acid does not dissolve it, but on digesting for an hour with acid of 1 to 
5 strength it goes into solution with evolution of acetic acid and formation 
of phenetidin sulphate. This acid solution on dilution gives a blue 
color with bromin water, but no precipitate, and it also gives a beautiful 
greenish-black iridescent precipitate with insufficient iodin solution to 
effect a complete conversion, but on adding excess the crystals change to 
an oily deep brownish-red resin. Acetphenetidin itself in aqueous solu- 
tion does not give any precipitate with iodin, neither is it precipitated 
by Mayer's reagent nor bromin water. 

If 0.1 gram of acetphenetidin is boiled for one minute with 1 mil con- 
centrated hydrochloric acid, the solution diluted with 10 mils water, and 
filtered, a ruby-red color should appear on adding 3 drops chromic acid 
(1-30). The anilides do not react in this way. 

It does not yield anilin on boiling with alkalies, but when warmed 
with alkali and chloroform there may develop a slight suggestion of iso- 
nitrile after several minutes. A solution resulting from boiling with 
alkali is not colored by the addition of sodium nitrite and dilute nitric 
acid and again boiled, but the solution obtained with acids gives a yellow 
precipitate with mercurous nitrate, which does not dissolve on boiling. 

Unconverted paraphenetidin may be detected in para-acetphenetidin 
by adding about .5 gram of the sample to 2.5 grams chloral hydrate, which 
has been heated to 100° C, when a rich violet to purple-violet color appears 
if the impurity is present. Acetphenetidin alone gives a pinkish tinge 
after several minutes. It may also be detected by shaking the sample 
with hot water, cooling, filtering, acidifying with dilute sulphuric acid, 
and adding a drop or two of iodin solution which will cause a precipitate 
in presence of phenetidin, but not with acetphenetidin. 

The presence of acetanilid in acetphenetidin is so readily detected 
that its use as an adulterant is now almost precluded. Acetphenetidin 
gives but a faint isonitrile reaction and this only on standing some minutes, 
while acetanilid gives it at once, and the "presence of but a trace can be 
detected by this alone. Acetphenetidin does not give the reaction with 
phenol and bleaching powder which is characteristic of the anilides; on 
boiling with alkali there is no separation of anilin and on hydrolysis with 
dilute sulphuric acid and the resultant acid solution diluted, there is no 
precipitate given by bromin water. Hence, if a sample is suspected of 
being adulterated the application of the above tests will be sufficient to 
establish the actual conditions. 

The question as to whether acetphenetidin is an acetanilid derivative 



856 ORGANIC SUBSTANCES 

is still open legally. When the Food and Drugs Act was written acetan- 
ilid was included in the list of inhibited drugs and the regulations for 
its enforcement enumerated acetphenetidin among its derivatives. One 
of the Attorney Generals, at the request of the Department of Agriculture, 
wrote an opinion, based on information submitted by the Bureau of 
Chemistry, in which the position was taken that a derivative need not 
be a substance actually derivable or preparable from another substance 
by chemical means, but may be such by chemical relationship or sub- 
stitution. On the other hand, the manufacturers take the position that 
acetphenetidin cannot be obtained from acetanilid, and therefore it 
should not be classified as its derivative. Looking at the space relation- 
ship of the two it is apparent that acetphenetidin might be called para- 
ethoxy acetanilid . 

OC2H5 



NHCOCH3 NHCOCH3 

Acetanilid Acetphenetidin 

As a matter of fact, however, acetphenetidin cannot be obtained directly 
from acetanilid by chemical means; by that is meant the introduction 
of the ethoxy group in the paraposition of the acetanilid molecule. It 
is, of course practicable to carry out the following train : acetanilid — * 
anilin — > phenol — > nitrophenol — > ethyoxy nitrophenol— »phenetidin— > acet- 
phenetidin. But this is one of the possibilities of synthetic chemistry, 
and is applicable to thousands of other substances. Synthetic chemistry 
has advanced to such a state that it is possible to work forward and back- 
ward through numberless compounds, to pass from the aliphatic to the 
aromatic series, and starting with sufficient quantity of a given substance 
to eventually arrive at countless others. Antipyrin, salicylic acid, oil 
of wintergreen, acetylsalicylic acid (aspirin), and many other well-known 
drugs are just as much derivatives of acetanilid as is acetphenetidin if 
the argument is valid that by any hook or crook you can obtain one sub- 
stance from another and call it a derivative of the original. 

Both the ortho and meta acetphenetidin are known and resemble each 
other closely in their physical properties. The meta is unimportant. 

The ortho and para bodies may be differentiated by the wide variance 
in their melting-points and the difference in the boiling-points of the phene- 
tidins which result on boiling with dilute hydrochloric acid and which 
may be separated from the acid liquid by rendering it alkaline and shaking 
out with ether or chloroform. The para compound is completely changed 
to acetic acid and p-phenetidin sulphate when digested for an hour with sul- 



ANILIDES AND PHENETIDINS 857 

phuric acid 1 in 5, but the ortho compound requires the action of stronger 
acid sn. gr. 1.575 for two hours at 90°. If in either case this resulting acid 
solution be diazotized, and then treated with an ammoniacal solution of 
naphthol-disulphonic acid, a fine reddish-yellow color appears in the case 
of the para body, and a cherry-red if the ortho is present. 

The best methods thus far evolved for the quantitative assay of acet- 
phenetidin mixtures are the result of the researches of Dr. W. 0. Emery 
and his associates. 

METHOD OF ANALYSIS OF MIXTURES CONTAINING CAFFEIN, ACET- 

PHENETIDIN, ETC. 

Determine the weight of 20 tablets, powder finely, and weigh out on 
a small (5.5 cm.) tared filter an amount equal to the average weight of 
1 tablet. Wash with successive small portions of chloroform to the amount 
of 40 to 50 mils sufficient at least to insure complete extraction of all caf- 
fein and acetphenetidin in the mixture, collecting solvent in a 200-mil 
Erlenmeyer. Distill off chloroform by means of a small flame until only* 
a few mils of solvent remain in the flask, using if possible in connection 
with this and similar operations a small spray trap. Add to the residual 
liquid 10 mils of dilate sulphuric acid (1 volume concentrated acid to 10 
of water) and digest on a steam- or vapor-bath until contents of flask have 
evaporated to about 5 mils, then add 10 mils of water and continue diges- 
tion until the residue again amounts to about 5 mils. The quantitative 
separation of caffein from acetphenetidin depending, as it does, on a com- 
plete hydrolysis of the latter into acetic acid and phenetidin, even- effort 
should be exerted to the end that all particles of acetphenetidin which 
may appear on the sides of the flask be gradually made to disappear in 
the acid liquid by a gentle rotation of flask during the process of digestion 
or by the addition of a few drops of alcohol or chloroform. 

Caffein 

Cool, pour, and rinse with water into a separatory funnel, so that the 
final volume does not greatly exceed 20 mils. Extract three times by 
means of vigorous shaking with thrice the volume of chloroform, in the 
present instance 60 mils. After clearing, pass through a small pledget 
of cotton (thrust up into the delivery tube of separator) and a small 
(5.5 cm.) filter into a 200-mil Erlenmeyer, being careful to recover any 
caffein which may cling to the apex of the delivery tube and edge of filter 
by washing with a little fresh chloroform. The pledget of cotton is 
removed by means of a wire and thrown into the separator on the com- 
pletion of each extraction, a fresh one being introduced into the delivery 
tube prior to each subsequent withdrawal of solvent. Distill the chloro- 



858 ORGANIC SUBSTANCES 

form from the combined extractions until the liquid is reduced to about 
10 mils then transfer to a small tared beaker or crystallizing dish by pour- 
ing and careful rinsing with small quantities of chloroform. Allow to 
evaporate spontaneously or at a moderate heat on a vapor bath to apparent 
dryness, partially covering the dish with a watch-glass toward the end of 
the operation in order to avoid possible loss by decrepitation. Remove 
dish from heat immediately on the appearance of a crystalline residue. 
Cool in desiccator and weigh as anhydrous cafTein. If caffein residue is 
impure due to fats, essential oils, coloring matter, etc., purify as directed 
under caffein-acetanilid mixtures. 

Acetphenetidin 

Wash filter used to dry chloroform in the preceding operation once 
with 5 mils of water, receiving latter in the separatory funnel containing 
the aqueous acid solution of phenetidin sulphate. Treat with successive 
small portions of solid sodium bicarbonate until an excess of this reagent, 
after complete neutralization of the sulphuric acid, persists at the bottom 
of mixture. Now add 60 mils of chloroform and for every 100 mg. of 
acetphenetidin known or believed to be present, 5 drops acetic anhydrid; 
shake for some time vigorously, allow to clear, then pass through cotton 
and a diy filter, as described for caffein, into a 200-mil Erlenmeyer. Dis- 
till over 50 mils of chloroform, make up to 60 mils with fresh solvent, and 
extract again. Distill over as before this time about 60 mils then make 
the third and final extraction. Distill the chloroform down to about 10 
mils, transfer residue by pouring and rinsing with small quantities of sol- 
vent into a tared 50-mil crystallizing dish, evaporate on steam- or vapor- 
bath to apparent dryness, finally removing any considerable excess of 
acetic anhydrid by repeated additions of about 1 mil of fresh chloroform, 
to which has been added a drop of alcohol. The acetphenetidin will 
finally appear as a whitish, crystalline mass, having usually a faint acetous 
odor. The latter will disappear completely on standing some hours in 
the open, or more quickly on a vacuum desiccator over lime. The residue 
is weighed at intervals until it suffers no further loss. 

CODEIN, CAFFEIN, AND ACETPHENETIDIN MIXTURE 
Codein 

Weigh out about 0.3500 gram of powdered material (if in pill or tablet 
form at least 10 of these should be reduced to powder), transfer to a sepa- 
rator funnel by means of 10 mils very dilute sulphuric acid (or sufficient 
to render the solution decidedly acid after neutralization of any carbonate 
that may be present), extract by means of vigorous shaking with 50 mils 



ANILIDES AND PHENETIDINS 859 

of chloroform. After clearing draw off the solvent, allowing it to run 
through a small (5.5 cm.) filter into a 200-mil Erlenmeyer. Distill off 
about 50 mils chloroform, using a small Bunsen flame. Extract a second 
and third time with same amount of solvent as first used. Allow the 
chloroform from each extraction to run into the Erlenmeyer, then distill 
off all but about 10 mils. Now add 10 mils dilute sulphuric acid (1 volume 
concentrated acid to 5 of water) and heat on steam-bath until the chloro- 
form has disappeared and only about 5 mils of the acid liquid remains, 
then treat as directed under caffein. 

Render the acid liquid in separator containing the codein sulphate 
neutral by the addition of solid sodium bicarbonate, wash out filter used 
in the proceding operation to clarify the chloroform, once with water, 
allowing latter to run into the separator, then reextract three separate 
times with 50 mils chloroform. Collect solvent as above directed in a 
second 200-mil Erlenmeyer, distilling off most of the liquid by the aid of 
gentle heat. Transfer residual chloroform to a small beaker or evapo- 
rating dish, using sufficient fresh chloroform for this purpose, heat gently 
over steam-bath to dryness, cool, and weigh as anhydrous codein. 

Caffein and Acetphenetidin 

The aqueous acid solution containing the caffein and phenetidin sul- 
phate is transferred to a separatory funnel and treated substantially as 
directed in the preceding method. 

SEPARATION OF ACETPHENETIDIN AND SALOL 

The gross separation of the mixtures from powder, tablets, or pill 
preparations is most conveniently effected by judicious treatment with 
chloroform. The separation of the two ingredients from each other can 
be accomplished in either one or two ways, depending : 

1st. On the acid hydrolysis of phenacetin, and salol remaining thereby 
unchanged, or: 

2d. On the alkaline hydrolysis of salol, the phenacetin in such case 
being unaffected. 

1st. Acid Hydrolysis 

Acetphenetidin 

If the sample is in pill or tablet form, ascertain the weight of 20 or 
more, reduce to a fine powder and transfer to a small tube or bottle which 
can be kept tightly closed with a cork or glass stopper. Weigh out on 
a small (5.5 cm.) tared filter an amount equal to or a convenient multiple 
of the average weight of such pill or tablet, wash with successive small 



860 ORGANIC SUBSTANCES 

portions of chloroform, in quantity about 40 to 50 mils, sufficient at least 
to insure complete extraction of all phenacetin and salol present in the 
mixture. Collect solvent in a tared 100-mil beaker and evaporate by 
means of a blast to apparent dryness. During this operation the beaker 
may be allowed to stand on a warm plate (50-60°) without danger of 
undue loss of solid substance. Allow to stand twenty-four hours at the 
ordinary temperature in the open, weigh several times or until the weight 
becomes practically constant, then transfer the residue, by dissolving in 
and washing with sufficient chloroform, to a 50-mil lipped Erlenmeyer, 
evaporate solvent by means of a blast and gentle heat, add 10 mils dilute 
sulphuric acid (1 : 10) and digest at full bath heat until the liquid is reduced 
one-half. Add 10 mils water, continue digestion as before, add a second 
10-mil portion of water and evaporate to 5 mils. Transfer the residual 
liquid pouring and washing with about 20 mils water to a separatory 
funnel of the Squibb type and extract in rotation with 15, 10, and 5 mils 
chloroform, first washing each portion as obtained with 5 mils water in 
a second separator to recover traces of phenetidin sulphate possibly taken 
up by the chloroform, finally rejecting this solvent, since it contains all 
the salol not carried off with the aqueous and acetous vapors eliminated 
during the process of digestion. 

To the aqueous-acid solution of phenetidin sulphate in the first sepa- 
ratory funnel, — into which also the wash water from the second separator 
has been poured,— add small portions of sodium bicarbonate until an 
excess of this reagent, after complete neutralization of sulphuric acid, 
persists at the bottom of separator. Now add 25 mils chloroform and 
for every 100 mg. acetphenetidin known or believed to be present 5 drops 
acetic anhydride, shake for some time vigorously, then pass the nearly 
clarified solvent into a second separator containing 5 mils water, shake, 
and receive the chloroform in a 200-mil Erlenmeyer, first passing it through 
a small (5.5 cm.) dry filter. Of this chloroform, which contains unex- 
pended acetic anhydride, distill off about 20 mils, return same to the first 
separator, augment with 5 mils fresh chloroform, and repeat the extrac- 
tion, washing and filtering as before, then collecting the solvent in the 
Erlenmeyer and again distilling until 25 mils chloroform are obtained. 
With this portion, make a third and final extraction, repeating the opera- 
tions of washing, filtering, and distilling to the point where about 5 mils 
chloroform remain in the Erlenmeyer. Transfer this chloroformic residue 
by pouring and washing with sufficient fresh chloroform to a tared 50- 
mil beaker or crystallizing dish, evaporate on a steam- or vapor-bath to 
apparent dryness, finally removing any pronounced excess of acetic 
anhydride by repeated addition of 1-mil portions of fresh chloroform to 
which a drop of alcohol has been added and subsequent evaporation. 
Allow the whitish crystalline residue of acetphenetidin to stand some 



ANILIDES AND PHENETIDINS 861 

time in the open, or better, in a vacuum desiccator over lime in order to 
dispel the last traces of anhydride. Weigh at intervals until constant. 

Salol 

To ascertain the quantity of salol present in the sample, subtract 
the weight of acetphenetidin from the combined weight of the two ingredi- 
ents determined in the early part of the procedure. 

Comments and Suggestions. — Tared niters for use in this and similar 
work may be conveniently prepared as follows: Fold, adjust in a small 
short-stemmed funnel, moisten and fit carefully so that the entire rim of 
filter closes snugly on the glass. After drying, keep in balance case or 
any suitable dust-proof container, and when needed weigh on a small 
metal support or glass tripod. It is self-evident that all weighings with 
tared filters should be made as nearly as possible under comparable con- 
ditions. If, for example, the first weight is taken when the hygrometer 
indicates a humidity of 50 per cent, the second weighing should if possible 
be made under approximately similar conditions. This is indispensable 
when it is desired to estimate the quantity of chloroform-insoluble residue, 
as in preparations containing sodium bicarbonate, sugar, starch, talc, or 
other more or less inert material. Experience has shown, however, that 
a variation in humidity up to 5 per cent in the two weighings would not 
be productive of material error. 

Before carrying out an extraction in a separatory funnel, the valve 
should first be " locked " with a drop of water prior to the introduction 
of any substance in solution, otherwise losses through capillarity may 
result. 

All distillations should be carried out over a wire gauze or asbestos 
provided with a small opening and subjected to a very gentle heat, the 
flask being connected with the condenser by means of a small spray trap, 
if available, similar to the type used in Kjeldahl work. 

Acetphenetidin being only moderately soluble in hot aqueous media 
is accordingly somewhat difficult of hydrolysis. In order to insure its 
complete conversion to phenetidin sulphate, special attention should be 
directed to the end that any visible particles of crystalline substance on 
the sides of flask during the early part of digestion should be gradually 
brought into solution by gently rotating the flask, and if necessary by the 
occasional addition of a few drops of chloroform. 

2d. Alkaline Hydrolysis 

Phenacetin 

On a small tared filter as above weigh out an amount of the powdered 
sample containing not more than 100 mg. salol, exhaust with chloroform 



862 ORGANIC SUBSTANCES 

as for acid hydrolysis, collecting the solvent (not more than 25 mils at 
one time) in a small (50-mil) Erlenmeyer. Add 10 mils 2.5 per cent sodium 
hydroxide solution and heat five minutes on a vapor- or steam-bath at 
the temperature of boiling water. At the end of this period remove and 
cool immediately to room temperature in running water in order to reduce 
to a minimum any tendency of the phenacetin to undergo partial hydrolysis. 
Transfer the liquid to a separatory funnel by pouring and washing with 
as little water as possible, finally rinsing out the flask with the first 20- 
mil portion of chloroform used in extraction. Extract the aqueous- 
alkaline solution with three 20-mil portions of chloroform, washing each 
portion as obtained consecutively in a second separator with 5 mils water, 
prior to passing through a small (5.5 cm.) dry filter into a 200-mil Erlen- 
meyer, from which the combined solvent is distilled down to a residue of 
about 5 mils. Transfer the latter by pouring and washing with sufficient 
fresh chloroform to a small tared beaker or crystallizing dish, evaporate 
the solvent on the steam-bath by the aid of a blast, cool, and weigh at 
intervals until constant. 



Salol 

Transfer both aqueous-alkaline solutions from the separatory funnels 
to a suitable (500 mil) glass-stoppered bottle, dilute with water to about 
200 mils, run in from a burette an excess (about 45 mils N/7) of potassium- 
bromide-bromate, follow with 10 mils cone, hydrochloric acid, close flask 
and shake one minute and then at intervals over a period of one-half 
hour. At the end of this time add 10 mils 15 per cent potassium iodide 
solution, agitating the closed flask at intervals for fifteen minutes. Titrate 
the free iodin with standard thiosulphate (preferably N/7), previously 
adjusted to the standard bromin solution, 1 mil of which is equivalent 
to 0.002548 gram salol. From the number of cubic centimeters of stand- 
ard bromin solution expended, calculate the salol on the basis of 12 atoms 
of bromin to 1 molecule of salol. 

Comments and Suggestions. — In order to facilitate the work and mini- 
mize errors due to recharging the burettes N/7 solutions are advocated 
in order that the volume of the thiosulphate rquired may not exceed 
the capacity of a 50-mil burette. 

The thiosulphate solution is standardized against pure iodin. The 
strength of the bromin solution may be checked if desired by the aid of 
acetanilid. 

The reactions involved in the foregoing procedure are: 

First, hydrolysis of salol to sodium phenolate and salicylate: 

C 6 H 4 (OH)COOC 6 H5+3NaOH=C6H4(ONa)COONa+C6H 5 DNa+2IfcO 



ANILIDES AND PHENETIDINS 863 

Phenol is attacked by bromin in excess to form symmetrical tri-bromo- 
phenolbromide : 

C 6 H 5 OH+4Br 2 = C 6 H 2 Br 3 OBr-f-4HBr 

while salicylic acid finally yields the same product, the tribromosalicylic 
acid first formed being very unstable and losing its carboxyl : 

C 6 H4(OH)COOH+4Br 2 = C 6 H 2 Br 3 OBr-|-4IIBr+C0 2 

The tribromophenolbromide thereupon reacts with hydroiodic acid 
to yield tribromophenol and free iodin : 

C 6 H 2 Br 3 OBr+2HI = C 6 H 2 Br 3 OH-f-HBr-r-I 2 

Accordingly, 12 atoms of bromin are required for every molecule of 
salol. 

ACETPHENETIDIN AND QUININ SULPHATE 

So far as the separation is concerned the method differs in no particular 
from that outlined for the combination of acetanilid and quinin sulphate. 
In the estimation, however, the procedure as applied to acetphenetidin 
is materially shortened, in that the physical properties of this substance 
permit its being weighed directly. 

Acetphenetidin 

Extract with three 50-mil portions of chloroform, washing each portion 
in rotation in a second separator (Squibb form) with 5 mils water and 
passing solvent after clearing through a pledget of cotton and small dry 
filter into a 200-mil Erlenmeyer. Distill the chloroform from the com- 
bined extractions down to about 10 mils, transfer the residue by pouring 
and washing with additional chloroform to a small tared crystallizing 
dish, allow to evaporate spontaneously or at a moderate heat on the 
steam-bath, cool and weigh at intervals until the loss does not exceed 
0.5 mg. 

Quinin Sulphate 

Follow directions as given under Acetanilid and Quinin Sulphate. 

Comments and Suggestions. — In all cases where cotton is used to 
remove suspended moisture from chloroform as suggested in the fore- 
going work, the material is inserted in the outlet tube, thus intercepting 
most of the moisture and any suspended matter that might otherwise 
clog the filter. 

Acetphenetidin and acetanilid are not dispensed together, but there 
is always the possibility that a determination of the antipyretic compounds 



864 ORGANIC SUBSTANCES 

in a mixture of these two antipyretics may become a matter of moment. 
Dr. Emery has developed a method for determining both acetanilid 
and acetphenetidin when they occur together and also a quantitative assay 
of a composite of the three antipyretics acetanilid, antipyrin and acet- 
phenetidin with caffein: 



ACETANILID AND ACETPHENETIDIN (PHENACETIN) IN MIXTURES. 

ACETPHENETIDIN 

Reagents 

(a) Purified Iodin. — Dissolve 2 parts of resublimed iodin and 1 of 
potassium iodid in 1 of water, pour the clear solution into a large volume 
of water, filter and wash the finely precipitated iodin several times on a 
porous plate with water. Dry in the air and finally in a desiccator over 
sulphuric acid where it is kept in a glass-stoppered weighing bottle. 

(b) Standard Sodium Thiosulphate Solution. — Dissolve 30 grams of 
crystallized sodium thiosulphate in water and dilute to 1 liter. Stand- 
ardize this solution against the purified iodin as follows : Weigh out about 
0.3 gram of the purified iodin in a small glass capsule (about \ inch high 
and f inch diameter) provided with a closely fitting glass cap or stopper, 
and place the capsule in a 200-mil Erlenmeyer flask containing 0.5 gram 
of potassium iodid dissolved in 10 mils of water. After complete solu- 
tion, titrate with the sodium thiosulphate solution, using 1 or 2 drops of 
starch solution as an indicator. 

(c) Standard Iodin Solution. — Dissolve 40 grams of potassium iodid 
in the least possible quantity of water, add 30 grams of the purified iodin 
and, after solution, dilute to 1 liter. Standardize 25 mils of this solu- 
tion against the standard sodium thiosulphate solution. 

Determination. — (1) Place 0.2 gram of the acetphenetidin-acetanilid 
mixture in a 50-mil lipped Erlenmeyer flask, add 2 mils of glacial acetic acid, 
heat gently over a wire gauze to complete solution, and dilute with 40 
mils of water, previousy warmed to 70° C. Transfer the clear liquid with 
two 10-mil portions of warm (40° C.) water to a glass-stoppered, 100-mil 
graduated flask containing 25 mils of the standard iodin solution warmed 
to 40° C. Stopper, mix thoroughly, then add 3 mils of concentrated 
hydrochloric acid, continue shaking until crystallization begins and then 
set aside to cool. If the ratio of acetphenetidin to acetanilid is equal 
to or greater than unity, crystalline scales will form almost immmediately 
on the addition of acid. As the proportion of acetanilid increases, however, 
the periodide tends to remain in the liquid state. In such cases, gentle 
agitation or rotation of the flask in water, warmed not to exceed 40° C, 
hastens the formation of crystals. When the contents of the flask are at 



ANILIDES AND PHENETIDINS 865 

room temperature, fill with water to within 2 to 3 mils of the mark, mix 
thoroughly, and allow to stand overnight. Fill to the mark with water, 
mix thoroughly, allow to stand thirty minutes, filter through a 5.5 cm. 
dry, closely fitting filter into a 50-mil graduated flask, rejecting, however, 
about 15 mils of the first runnings, but reserving them for the recovery of 
the acetanilid. Transfer the 50-mil aliquot to a 200-mil Erlenmeyer 
flask and titrate with the standard sodium thio sulphate solution. Cal- 
culate the amount of acetphenetidin from the following formula : 

Acetphenetidin = 1(0.0899 XN) 

0.0889 = the quantity of acetphenetidin contained in 1 mil of a normal 
solution of this substance; 
N = the normality of the standard sodium thiosulphate solution 

employed; and 
I = the number of mils of the standard sodium thiosulphate solution 
corresponding to the iodin combined with the acetphenetidin. 

The formula of the precipitated periodide, which constitutes the basis for 
the above determination, is (C 2 H 5 • C 6 HiNH • COCHs^HI • I4. 

(2) The gravimetric determination of acetphenetidin may, if desired, 
be effected as follows : Filter off the periodide, preferably by suction, wash 
with 10-15 mils of the standard iodin solution, then transfer together with 
the filter to a separatory funnel, using not over 50 mils of water. Remove 
both free and added iodin with a few small crystals of sodium sulphite 
and extract the liquid with three 50-mil portions of chloroform, washing 
each portion subsequently into a second separatory funnel with 5 mils 
of water. After washing and clearing, filter the chloroform solution 
through a dry 5.5-cm. filter into a 200-mil Erlenmeyer flask, distill off 
most of the chloroform, transfer the residual solution (5 to 10 mils), by 
means of a little chloroform, to a small, tared beaker or crystallizing dish, 
evaporate to dryness on a steam-bath, cool, and weigh. 

For the identification of acetphenetidin, either alone or in admixture 
with acetanilid, the following test will be found of value: To 1 to 2 mg. 
of the sample in a test-tube add a drop of acetic acid and 0.5 mil of N/10 
iodin, warm the mixture to about 40° C, then add a drop of concentrated 
hydrochloric acid. If acetphenetidin alone is present, its periodide sepa- 
rates almost immediately in the form of reddish-brown leaflets or needle- 
like crystals. If the sample consists largely of acetanilid, the separation 
takes place on cooling and shaking the liquid. In the globules, which, 
on vigorous shaking, gradually become crystalline, this test is so delicate 
that as little as 0.5 mg. of acetphenetidin may, if alone, be detected in 
the form of its characteristic periodide. 



866 ORGANIC SUBSTANCES 



Acetanilid 



(1) If the combined weight of the acetphenetidin-acetanilid mix- 
ture is known, determine that of the latter ingredient by difference; or, 
(2) Determine it directly from a second aliquot of the filtrate from the 
acetphenetidin in the foregoing as follows: 

Pipette 25 to 30 mils of the clear liquid into a separatory funnel, 
decolorize with solid sodium sulphite and solid sodium bicarbonate in 
slight excess, add 1 or 2 drops of acetic anhydride, then extract with three 
60-mil portions of chloroform, passing the chloroform solution, when 
cleared, through a small, dry filter into a 200-mil Erlenmeyer flask, and 
distill the chloroform, by the aid of gentle heat, to about 20 mils. Add 
10 mils of sulphuric acid (1 : 10) and digest on a steam-bath until the resi- 
due has been reduced one-half, add 20 mils of water and continue the 
digestion for an hour: then add a second 20-mil portion of water and 
10 mils of concentrated hydrochloric acid, titrate very slowly, drop by drop, 
with the standard bromide-bromate solution, until a faint yellow color 
remains. While adding this reagent, rotate the flask sufficiently to agglom- 
erate the precipitated tribromanilin. Calculate the amount of acet- 
anilid present. 

If the preparation contains caffein or antipyrin or both in addition 
to acetanilid and acetphenetidin, proceed as follows: (1) Digest the 
mixture by heating with dilute sulphuric acid to convert acetphenetidin 
and acetanilid into phenetidin and anilin sulphates, respectively; (2) 
Separate the caffein and antipyrin by extraction with chloroform; (3) 
Re-form acetphenetidin and acetanilid by treating the solution of the 
corresponding sulphates with solid sodium bicarbonate in slight excess, 
then add a few drops of acetic anhydride and extract with chloroform ; (4) 
Weigh the residue of acetanilid and acetphenetidin, then dissolve in 
glacial acetic acid and pour into standard iodin solution using precautions 
given above for precipitating the periodide of acetphenetidin. Titrate an 
aliquot and calculate the acetphenetidin; (5) Determine the acetanilid by 
difference or directly in an aliquot of the clear liquid by destroying the 
excess of iodin, extracting with chloroform in the presence of acetic 
anhydride, converting the residue to anilin sulphate by digestion with 
dilute sulphuric acid, and finally titrating the anilin sulphate with bromide- 
bromate reagent; (6) The caffein and antipyrin can be separated from 
each other by precipitation of the latter by picric acid. 



ANILIDES AND PHENETIDINS 867 

Methyl Acetphenetidin 

/OC2H5 
C 6 H4< 

x N(CH 3 )COCH 3 

melts 40° C, distills 300°, and crystallizes on standing. It is moderately- 
soluble in water, soluble in alcohol, ether, benzol, and chloroform, and is 
used as an hyponotic, 

Methoxy acetphenetidin, Kryofine. 

Kryofine is a condensation product of paraphenetidin and methyl- 
gly colic acid. 

/OC2H5 
CeH4\ 

\NHCOCH3OCH3 

It is a white crystalline substance, melting 98°, slightly soluble in water, 
readily in alcohol. 

Amino Acetphenetidin. Phenocoll or Phenamine 
,OC 2 H 5 



CgHk 

^NHCOCH 2 NH 2 

Phenocoll is prepared by the action of chloracetyl chloride on phene- 
tidin and treating the product of the reaction with ammonia. It is a much 
stronger base than acetphenetidin and forms salts with acids. 

The free base (phenocoll) obtained by precipitating the aqueous solu- 
tion with fixed alkalies or their carbonates forms white, matted needles, 
containing one molecule of water. In its hydrated condition it melts at 
95° C. while the anhydrous base melts at 100.5° C. It is stable and not 
chemically affected by acids or alkalies unless subjected to prolonged 
boiling with these reagents, by which phenocoll is split into phenetidin 
and glycocoll. 

Phenocoll is usually dispensed or sold in the form of the hydrochloride. 

Phenocoll salicylate or salocoll is prepared by neutralizing a hot aqueous 
solution of salicylic acid with phenocoll and cooling the solution. 

It forms fine, white crystalline needles, having a sweetish taste, spar- 
ingly soluble in cold water (1 : 200), readily soluble in hot water. It 
gives a violet reaction with ferric chloride. 

It is incompatible with soluble hydroxides and carbonates and with 
bodies which are incompatible with the salicylates in general. 

It is used in rheumatism, gout, chorea, pleuritis, and fevers, especially 
in influenza. 



868 ORGANIC SUBSTANCES 






Iodophenin is a product purporting to be a periodide of acetphenet- 
idin. It is a brownish-black crystalline substance, melting 130-131°, 
and soluble in alcohol and water. It is employed chiefly for its anti- 
septic value, though it is claimed that it possesses some value as an internal 
remedy in articular rheumatism. 

Thymacetin 

,OC 2 H5 



/ /CH3 

Thvmacetin is credited with the composition CeH 2 ^ ( 

X C 3 H 7 

NHCOCH3 

It is a white crystalline powder, melting 136°, soluble in alcohol and ether 
and slightly in water. 

Phesin 

Phesin is the name given to a sodium sulpho product prepared from 
acetphenetidin. It is soluble in water and is used as an antipyretic. 

The drug trade has been flooded with a quantity of phenetidin deriva- 
tives closely allied to acetphenetidin. They differ from acetphenetidin 
in that some other acid radicle is substituted for the acetyl group, or the 
phenetidin complex is esterified with carbonic acid and another base. 

Formyl Phenetidin 
,OC 2 H 5 



C6H4X 

\NHCOH 

Formylphenetidin forms colorless crystals, melting 60°, soluble in 
alcohol and ether but insoluble in water. It is devoid of antipyretic 
properties, but has been suggested as an antidote for strychnin poisoning 
and as an antiseptic. 

Lactophenin 

Lactophenin is lactylparaphenetidin, 

CeKU • OC2H5 • NH(CH 3 ■ CHOH • CO) 

Lactophenin occurs as a white crystalline, odorless powder, of slightly 
bitter taste and neutral reaction. It melts at 117.5° to 118° C. It is 
rather difficultly soluble in cold water (1 : 330), and is soluble in 55 parts 
of boiling water. It is soluble in 8.5 parts of alcohol and is not precipi- 



ANILIDES AND PHENETIDINS 869 

tated from this solution by water. In ether and petroleum ether it is 
difficultly soluble. 

On boiling 0.2 gram of lactophenin with 2 mils hydrochloric acid for 
one minute, then diluting the solution with 20 mils water and filtering 
when cold the filtrate will become colored a ruby red on the addition of 
chromic acid solution. 

On dissolving 0.1 gram lactophenin in 10 mils hot water, and filtering 
when cold, the filtrate on the addition of bromin water, should develop 
a decided turbidity which disappears on the addition of much water. 



Triphenin— Propionyl-phenetidin, C 6 H4(OC2H5)NH(CH 3 CH 2 CO) 

is a derivative of paraphenetidin, differing from acetphenetidin in 
that the acetic acid residue has been replaced by the propanoic acid 
residue, (CH3CH2CO). 

It is a white, shining crystalline powder, melting at 120° C, odorless 
and faintly bitter. It is practically insoluble in water, requiring 2000 
parts, but soluble in alcohol and ether. 

In general it responds to the tests for acetphenetidin. From this 
it may be distinguished by its melting-point, and by identifying the pro- 
panoic acid evolved when heated with 50 per cent sulphuric acid. 

Triphenin is antipyretic, analgesic, and hypnotic. 



Salicylparaphenetidin. Malakin 
.OC2H5 



CeH4< 

^NHCOC 6 H 4 OH 

Malakin forms bright-yellow needles, melting 92° C, soluble in hot 
alcohol and alkali carbonates, insoluble in water. It is antipyretic, 
analgesic, and teniacidal, and is used in the expulsion of tapeworm. 



Phenetidin Salicylacetate or Acetosalicylate, Phenosal 
/OC2H5 

C6H4<f 

x NHCOCH 2 OC 6 H40H 

Phenosal is a white crystalline substance, melting 182°, soluble in 
alcohol and ether and slightly in water. It is an antipyretic, antirheu- 
matic, and antineuralgic. 



870 ORGANIC SUBSTANCES 

Isovalerylparaphenetidin. Sedatin 
/OC2H5 

\NHC5H9O 

Sedatin forms lustrous, colorless needles soluble in alcohol and chloro- 
form, slightly in ether and insoluble in water. It is used as a sedative 
and nervine. 

Phenetidin Amygdolate. Amygdophenin 
/OC2H5 

C6H4<^ 

/ x NHCO CHOH C 6 H 5 

Amygdophenin forms white leaflets, melting 140-141°, soluble in ether 
and slightly in water. It is used as an antineuralgic. 

Acetophenonphenetidin Citrate. Malarin 

Malarin forms colorless crystals soluble in hot water and alkalies. 
Citrophen and apolysin are claimed to be compounds of citric acid and 
phenetidin. Both are soluble in water and are antipyretics and anti- 
neuralgics. 

Hypnoacetin — Acetophenone Acetylparamidophenol Ester 
C 6 H 4 (OCH 2 COC 6 H 5 ) (NHCOCH3) 

This body forms leaflets readily soluble in alcohol but insoluble in 
water, and is sometimes used as an hypnotic and antiseptic. 

Eupyrin— Vanillin-etfcylcarbonate-para-phenetidin 
C 6 H 4 (OC 2 H 5 )N : CR C 6 H 3 (OCOOC 2 H 5 )OCH 3 ) 

It occurs in light yellow, needle-shaped crystals, melting at 87 to 88° C. 
tasteless, with faint odor of vanillin. It is insoluble in cold water and 
in cold alcohol, readily soluble in warm alcohol and in ether or chloroform. 

Concentrated sulphuric acid is colored by eupyrin greenish-yellow 
in the cold and dark brown on heating to the boiling-point. 

Thermodin. Acetylparaethoxy-phenyl urethane, C 6 H4(OC2H5)[(N(COOC 2 H 5 )(COCH 3 )] 

It forms colorless, odorless, and tasteless crystals, melting at 86 to 
88° C. It is practically insoluble in cold water (1 : 2600); soluble in 
450 parts of boiling water. 

If 0.5 gram of thermodin, 5 mils sulphuric acid, and 5 mils of alcohol 
are mixed and warmed gently, the odor of ethyl acetate is developed. A 






ANILIDES AND PHENETIDINS 871 

solution of 0.5 gram of thermodin in 5 mils of sulphuric acid on the addition 
of 0.2 gram of sucrose, assumes a red color, becoming more intense on 
standing. If 0.5 gram of thermodin is boiled with 3 mils of hydrochloric 
acid during one minute, then mixed with 5 mils phenol solution 1 : 20, 
and a solution of chlorinated lime added, an onion-red color appears which 
changes to blue on supersaturation with ammonium hydroxide. 
Thermodin is an analgesic, antipyretic, and antiseptic. 

Pyrantin. Paraethoxyphenylsuccinimide 
,OC 2 H 5 



a/ 



N(CH 2 CO) 2 

Pyrantin forms colorless needles, melting 155° C, soluble in alcohol, 
slightly in cold water and insoluble in ether. 

A sodium salt of pyrantin is sold as Pyrantin Soluble. 

Paraphenetidin Carbamide. Dulcin Sucrol or Valzin. 
/NH 2 

c=o 
\nhc 6 h 4 oc 2 h 5 . 

Dulcin is sweet-tasting substance, melting 173°. It is sparingly soluble 
in cold water, more so in hot, and readily in alcohol and ether. It is not 
removed by alkalies from its solution in ether and hence differs from sac- 
charin for which it may be substituted. 

Chinaphenin. Phenetidinquinin-carbonic Ester 

Chinaphenin has already been described under the derivatives of 
quinin. 

Diacetyl Paramido Phenol — Anapyralgin 
OCO CH 3 



I 

NH COCH3 

This body, which is prepared by the action of acetic anhydride on 
paramino phenol, has a limited use as an antipyretic and analgesic, and 
will be found as a component of headache mixtures. It forms white 



872 ORGANIC SUBSTANCES 

crystals, melting 118°, readily soluble in ether, alcohol, and warm water, 
fairly soluble in chloroform and benzol, and slightly in petroleum ether. 
It is removed from the aqueous solution by ether. It sublimes very 
slowly at the temperature of the water-bath. 

The aqueous solution is neutral to litmus, it is turned a deep bronze- 
green color with ferric chloride, which gradually becomes brownish with 
increasing turbidity. It gives no precipitates with Mayer's reagent, iodin, 
bichromate, or potassium f errocyanide ; brornin water gives a clear solu- 
tion but on standing a cloudiness appears. 

When heated with concentrated sulphuric acid and subsequently 
treated with alcohol and warmed, the odor of ethyl acetate is evolved. 
Acetphenetidin when warmed with sulphuric acid, cooled, and then treated 
with a little water will give off an ethyl acetate odor, without the addition 
of alcohol. It does not give the isonitrile test. 

The solution of this substance in concentrated sulphuric acid is 
uncolored, bichromate produces a non-characteristic olive green color 
and molybdic oxide a greenish blue. Concentrated nitric acid produces 
a violent reaction and the solution is yellowish brown. On evaporating 
the acid and subsequently treating with alcoholic potash there is no 
reaction of note. 

When treated for two hours with dilute sulphuric acid 1 in 5 and then 
diluted, the solution does not yield a precipitate with iodin, but does with 
brornin water or bromide-bromate reagent. In both these reactions 
it differs markedly from acetphenetidin. The dilute solution reacts with 
ferric chloride, turning a dirty green, which darkens rapidly to a purplish 
brown. On neutralizing the acid solution with potassium hydroxide it 
becomes pale violet in color. This alkaline solution on long wanning 
with chloroform gives a slight odor of isonitrile. 



CHAPTER XXII 
ORGANIC ARSENIC COMPOUNDS 

From the point of view of the pharmaceutical chemist the organic 
compounds containing arsenic may be divided into two classes, those of 
definite chemical composition and those of uncertain or doubtful individual 
identity. Those of definite chemical composition are of course divisible 
into a number of different classes, depending on then structural form. 
To the second or uncertain class belong all those substances such as the 
peptonates, and those whose combination with animal acids is either 
dependent on some third body, or which may be readily separated into 
their compounds by mechanical means, and are therefore more on the 
order of mixtures. 

The simplest organic arsenic compounds are the arsines, AsR3 ; which 
correspond to the tertiary amines. They are obtained by treating arseni- 
ous chloride with the zinc alkyl compounds or by heating the alkyl 
iodides with sodium arsenite. Tertiary arsines combine directly with 
two atoms of a halogen, forming compounds such as triethylarsine dichlor- 
ide, As(C2H5)sCl2, in which the arsenic atom is pentavalent. These latter 
substances may be decomposed on heating, 3 r ielding a halogen derivative 
of a secondary arsine, As(C2H5)3Cl2 = As(C2H5)2Cl+C2H5Cl, and the 
secondary compound will add halogens to form As^H^Oa, which on 
heating decomposes into a dihalogen derivative of a primaiy arsine, 
As(C2H5)Cl2+C2H 5 Cl. The primary and secondary arsines are them- 
selves unknown. 



CACODYLIC ACID 

When a mixture of equal parts of arsenic trioxide and potassium 
acetate is subjected to dry distillation dimethyl arsine oxide or cacodyl 
oxide is formed. 

As(CH 3 K 
As 2 3 +4CH3COOK = >0+2K 2 C0 3 +2C0 2 

As(CH3) 2 X 

It is an intensely evil-smelling liquid, boiling 150° C, extremely poisonous, 

873 



874 ORGANIC SUBSTANCES 

and unites with acids forming salts, As(CH 3 )2Cl. On oxidation with mer- 
curic oxide cacodylic acid is produced. 

As(CH 3 ) 2 v 

>0+2HgO+H 2 = 2(CH 3 ) 2 AsO • OH+2Hg 
As(CH 3 ) 2 X 

Cacodylic acid is a crystalline, odorless, deliquescent substance, soluble 
in water and alcohol, and melts 200° C. It is monobasic, acid to litmus 
and phenolphthalein, and neutral to methyl orange. If 1 mil of the solu- 
tion of the acid is treated with 10 mils of a solution of hypophosphorous 
acid containing hydrochloric acid, stoppered and allowed to stand, the 
odor of cacodyl will be noted on uncorking the flask. 

The cacodyl complex is decomposed with considerable difficulty. If 
cacodylic acid or its salts are fused with alkali and afterward dissolved 
in water, acidulated, and subjected" to the action of hydrogen sulphide, 
there is considerable precipitation of the sulphide, but the odor of cacodyl 
is apparent. Similar conditions will be noted in the Marsh test, the 
mirror forms but there is an odor of cacodyl evolved. 

The cacodylates are not of great importance medicinally at the present 
time. They may be used in cases where an arsenic tonic is indicated, 
such as malaria, diabetes, anemia, chlorosis, etc., and in veterinary practice 
the sodium salt has been found useful as a remedy for " loco v poisoning. 

A number of salts have been prepared, including the sodium, potassium, 
lithium, calcium, magnesium, iron, manganese, silver, and mercury. 
Some of these, especially with the heavier metals, are of doubtful composi- 
tion; e.g., the iron salt may be simply a mixture of iron oxide and the acid. 

The sodium salt is the best known commercial compound. It may 
contain varying amounts of water, but as marketed it usually contains 
three molecules. 

It is a white powder, very soluble in water, forming needle-shaped crys- 
tals, hygroscopic, but otherwise of marked stability. The aqueous solution 
is alkaline toward litmus, but nearly neutral toward phenolphthalein. 

On addition of silver nitrate to a solution of 1 gram of sodium 
cacodylate in 20 mils of water, a white precipitate is formed which is solu- 
ble in nitric acid and in ammonia water. If to 1 mil of a 1 per cent solu- 
tion of sodium cacodylate 10 mils of hypophosphorous acid are added 
and put aside for one hour in a closed container, a disgusting odor of 
cacodyl is apparent. 

If calcium chloride solution is added to a solution of sodium cacody- 
late (1 : 20) no precipitate will be produced in the cold nor on warming 
(distinction from sodium menomethyl arsenate). 

Estimation. — A weighed quantity (approximately 1 gram) is dissolved 
in 25 mils of water, one drop of methyl orange added, and then normal 



ORGANIC ARSENIC COMPOUNDS 875 

hydrochloric acid added until a faint pink color appears; 1 mil normal 
hydrochloric acid = 0.2125 gram of sodium cacodylate. If to the finished 
titration phenolphthalein is added, a volume of normal potassium hydroxide 
equal to the volume of normal acid used should be required to produce 
a red color; (CE^AsC-OH being a monobasic acid toward phenol- 
phthalein. 

The monomethyl acid, CHsAsO(OH)2, or arsonic acid, is known in 
the form of its sodium salt, CH3AsO(ONa)2, called Arrhenal or New 
Cacodyle, which is prepared by the interaction of methyl iodide and sodium 
arsenate in the presence of an excess of alkali. 

Arrhenal is soluble about 1 in 1 in water, only slightly in alcohol 90 
per cent. A solution of the salt (strongly acidified) with hydrogen sul- 
phide gives a precipitate of mono- and disulphide of methyl-arsine. 
Arrhenal solutions do not precipitate with baryta water (sodium cacody- 
late does), nor with magnesia mixtures (nor does sodium cacodylate), 
nor by cold solution of calcium chloride (nor does sodium cacodylate), 
but are precipitated by nitrates of silver (white silky precipitate; sodium 
cacodylate none) and mercury (also sodium cacodylate; both yellow, 
arrhenal the darker of the two). Mercuric chloride gives reddish-yellow 
precipitate with arrhenal, and a white precipitate with sodium cacody- 
late. Sodium p-aminophenylarsonate gives a white precipitate with these 
reagents in every case. Arrhenal may be estimated by dissolving about 
0.2 gram in 1 to 2 mils of water and adding 15 to 20 mils of hydrochloric 
and hypophosphorous acid mixture. After twelve hours dilute with 
15 to 20 mils of water and filter, washing the residue with water. To the 
filter and its contents add a known excess of N/10 iodin solution, shake 
well, and titrate excess with sodium thio sulphate. 

• CH 3 As+4I+3H20 = CH 3 AsO(OH)2+4HI 

The black body CH3AS is quantitatively produced from 1 molecule 
CH3 AsO • (ONa)2, therefore 4 atoms of iodin = 1 molecule arrhenal. 
Bougault suggested this reagent for testing for traces of arsenic in glycerin 
(arsenite or arsenate) and for cacodylate. For the latter it is exceed- 
ingly delicate. 

To prepare the test, dissolve 20 grams sodium hypophosphite in 20 
mils water and add 200 mils hydrochloric acid (1.17 sp. gr.). Sodium 
chloride is thrown out and removed. To apply the test, 5 mils glycerin 
is mixed with 10 mils of the reagent. Place in water-bath — brown deposit. 

This methylarsine, CH3AS, is also obtainable by action of sodium 
hypophosphite and sulphuric acid on sodium cacodylate, 

2H3PO2 + AsCH 3 0(OH) = 2H3PO3 +CH 3 As +H 2 0, 

as a yellow oil insoluble in water, with strong garlic odor. 



876 ORGANIC SUBSTANCES 



Arsanilic Acid, C 6 H 4 (NH 2 )(As(OH) 2 ) 

Arsanilic acid is prepared by condensing anilin and arsenic acid. 
The sodium salt, C 6 H4(NH 2 )(AsO-OH-ONa), crystallizes with 5 mole- 
cules of water, 3 of which are lost by efflorescence. The arsenic content 
of the commercial article varies somewhat and the product is known 
by several names, Arsanin, Atoxyl, Soamin and Sodium arsanilate, all of 
which may differ slightly in their amounts of arsenic. 

An acid solution of sodium arsanilate is not affected by hydrogen 
sulphide in the cold, but precipitation is complete when the solution is 
warmed. Iodin is liberated when a solution is treated with hydro- 
chloric acid and potassium iodide, and the resulting solution is precipi- 
tated by hydrogen sulphide. 

Mineral acids cause a precipitation of white arsanilic acid, and silver 
nitrate throws out a white precipitate. An aqueous solution when treated 
with hydrochloric acid and potassium nitrate, gives a deep red color with 
a solution of beta-naphthol in sodium hydroxide. 

Solutions of sodium arsanilate give a yellow precipitate or a yellow 
color with calcium hypochlorite and a blue color with the same reagent 
in the presence of phenol. With reducing agents such as zinc and sul- 
phuric acid in the cold or stannous chloride or hypophosphorous acid in 
strong hydrochloric acid on warming, a yellow precipitate is obtained. 
On conversion to arsendiazo benzene by adding a few drops of 0.5 per cent 
solution of sodium nitrite and a little sulphuric acid, the solution will 
give a carmine-red color with acetaldehyde, followed by a few drops of 
potassium hydroxide, and with an excess of alkali the color changes to 
yellow. 



Arsacetin, C 6 H4(NHCH 3 CO) (AsO • OH • ONa) +4H 2 

Arsacetin is the sodium salt of a derivative of arsanilic acid. It is 
a white, crystalline substance, odorless, tasteless, and fairly soluble in 
water. The aqueous solution gives a white precipitate with silver nitrate. 

If a mixture of 0.1 gram arsacetin, 0.5 gram dry sodium carbonate, 
and 0.5 gram potassium nitrate are melted in a porcelain crucible, the 
white mass dissolved in 10 mils water and the solution neutralized with 
dilute nitric acid, a portion of the liquid yields a white crystalline pre- 
cipitate on addition of an equal volume of magnesia mixture. A further 
portion of the neutral liquid furnishes a brown precipitate, soluble in 
ammonia and also in nitric acid, on addition of a few drops of silver nitrate 
solution. 

If 0.2 gram arsacetin is heated with 5 mils alcohol and 5 mils sulphuric 
acid, the odor of acetic ether is developed. 



ORGANIC ARSENIC COMPOUNDS 877 

The aqueous solution of arsacetin (1 : 10) should be clear and color- 
less, possess at most a faintly acid reaction, and after addition of 5 mils 
dilute hydrochloric acid the liquid should not be altered by freshly pre- 
pared hydrogen sulphide solution. 

If 0.1 gram arsacetin is dissolved in 20 mils water, 1 mil dilute hydro- 
chloric acid and 2 drops sodium nitrite solution added and filtered, an 
alkaline beta-naphthol solution should produce no red coloration in the 
nitrate. An aqueous solution (1 : 20) to which 20 mils magnesia mix- 
ture is added should afford no turbidity or precipitate within two hours. 

Five-tenths gram powdered arsacetin, after heating for four hours 
at 110-120° C, should show a loss in weight of about 20 per cent. 

In order to determine the arsenic in atoxyl and arsacetin Rupp and 
Lehmann 1 heat 0.2 gram of the substance with 10 mils of concentrated 
sulphuric acid to 70°, and then 1 gram of potassium permanganate is 
added in small portions with agitation, followed by 5-10 mils hydrogen 
peroxide until the solution is clear. It is then diluted with 20 mils of 
water, boiled ten to fifteen minutes and diluted with 50 mils water. After 
cooling 2 grams of potassium iodide are added and after standing one 
hour the liberated iodin is titrated with N/10 thiosulphate. 

ARSENOPHENOL-AMINES 

These bodies contain two atoms of arsenic believed to be coupled 
together by a double linkage, the arsenobenzene, CeH 5 • As = AsCgHs, 
comparable with azobenzene, C6H5N = NCeH5. 

Arsenphenol-Amine Hydrochloride. Salvarsan. Arsphenamine 

This interesting body, originally exploited as Erlich's " 606," is 3- 
diamino-4-dihydroxy-l arsenobenzene hydrochloride 

HC1NH 2 • OH • CeHsAs = AsC 6 H 3 • OH • NH 2 • HCL+2H 2 

The commercial product contains 29.5 to 31.57 per cent arsenic. 

It is a yellow, crystalline, hygroscopic powder, very unstable in air. 
It is readily soluble in water, yielding a solution with an acid reaction. 
The addition of sodium hydroxide solution to an aqueous solution in the 
ratio of two molecules of sodium hydroxide to one of salvarsan, precipitates 
the free base (NH 2 • OH • CeHs As : As • C 6 H 3 • OH • NH 2 ) . On the addi- 
tion of an aqueous solution of sodium carbonate to an aqueous solution 
of salvarsan, a precipitate is produced which is insoluble in an excess of 
the reagent. 

When heated with an alkaline solution of potassium permanganate 
the permanganate solution is reduced and ammonia given off. 

1 Apoth. Zeit., 1911,26,200. 



878 ORGANIC SUBSTANCES 

The addition of ferric chloride solution to an aqueous solution of 
salvarsan produces a brownish-violet color, which gradually changes to 
a dark red; finally the liquid becomes turbid. 

Silver nitrate solution added to an aqueous solution of salvarsan acidi- 
fied with dilute nitric acid yields a dark-yellow precipitate which rapidly 
becomes black. 

The addition of concentrated nitric acid to an aqueous solution pro- 
duces a yellowish-white precipitate. On further addition of the acid 
the precipitate redissolves and the solution becomes dark red. 

Salvarsan gives a green color with nickel salts, pink with cobalt, blue 
with copper, and a yellow precipitate with picric acid. 

Neosalvarsan — Neoarsphenamine 

Neosalvarsan is a mixture of sodium 3-diamino-4-dihydroxy-l-arseno- 
benzene-methanal-sulphoxylate, NH2 • OH • C6H3 -As : As • C6H3 • OH • 
NH(CH20)OSNa, with inert inorganic salts. The arsenic content of three 
parts of neosalvarsan is approximately equal to that of 2 parts of salvarsan. 

It is an orange-yellow powder possessing a peculiar odor. It is very 
unstable in the air. It is readily soluble in water, yielding a yellow solu- 
tion which is neutral toward litmus. Upon standing the aqueous solu- 
tion becomes dark brown, forming a brown precipitate. 

A freshly prepared aqueous solution (1 in 100) yields a precipitate on 
the addition of mineral acids, a brown color and black precipitate with 
silver nitrate, and with ferric chloride a violet color should be produced, 
which soon changes to a dark red. 

If to 10 mils of the aqueous solution 5 mils of diluted hydrochloric 
acid are added and the mixture heated, sulphur dioxide will be evolved. 
If to 10 mils of the aqueous solution 5 mils of diluted hydrochloric acid 
are added, the precipitate collected on a filter and treated with zinc dust 
and warmed with diluted hydrochloric acid in a test-tube, and if paper 
moistened with a 5 per cent cadmium chloride solution is held in the 
mouth of the tube, the paper should be stained yellow within a few minutes 
(distinction from salvarsan). 

If to 10 mils of the aqueous solution 5 mils of diluted hydrochloric 
acid are added, the precipitate removed by filtration, 2 mils of barium 
chloride test solution added to the filtrate, the mixture allowed to stand 
for twelve hours, the precipitate of barium sulphate removed by filtration, 
5 mils of nitric acid added to the filtrate, the mixture boiled and evapo- 
rated to dryness, the residue should not be completely soluble in 50 mils 
of hot water slightly acidified with hydrochloric acid. 

These remedies are usually dispensed in sealed tubes containing vary- 
ing quantities or dosages. 



ORGANIC ARSENIC COMPOUNDS 879 

Lehmann x recommends the following method for estimating the arsenic 
in salvarsan and neosalvarsan : 0.2 gram is weighed into a 200-mil glass- 
stoppered flask of Erlenmeyer shape (iodin-number flask), 1 gram potas- 
sium permanganate added, 5 mils dilute sulphuric acid and the mixture 
agitated repeatedly over a period of ten minutes. Ten mils of concen- 
trated sulphuric acid are slowly added, rotating the flask meanwhile, 
followed by 5 to 10 mils hydrogen peroxide solution added drop by drop 
until the manganese precipitate disappears and a clear solution results. 
Twenty-five mils of water are now added and the solution boiled for ten 
minutes, 2 then diluted cautiously with 50 mils water. After cooling 
2.5 grams of potassium iodide are added and the flask stoppered and allowed 
to stand one hour, the free iodin being titrated at the end of that time 
with N/10 sodium thiosulphate. One mil = .003748 gram arsenic. 

GRAVIMETRIC DETERMINATION OF ARSENIC IN SALVARSAN 

Meyers and DuMez 3 obtained results with this method which closely 
parallel those obtained with Lehmann's procedure. 

Weigh out accurately about 0.2 gram of the product and transfer it 
to a Kjeldahl flask of 300 mils' capacity. Add 1.5 grams of a mixture 
of equal parts of sodium nitrate and potassium nitrate, 200 mils of dis- 
tilled water and 5 mils concentrated sulphuric acid. Heat the mixture 
slowly under a hood to allow the escape of the nitric acid fumes. Add 
a small quantity of concentrated or fuming nitric acid from time to time, 
until oxidation is completed, which is generally indicated by the disap- 
pearance of the yellow color. 4 Continue the digestion until the volume 
of the liquid has been reduced to about 15 mils, 5 cool, add 100 mils of dis- 
tilled water, and again concentrate to about 15 mils in order to remove 
the last traces of nitric acid. If the product has been completely oxidized 
and all traces of nitric acid have been removed, the liquid will be water- 
clear at this point. After cooling, cautiously neutralize the liquid with 
strong ammonia water and transfer it to a 300-mil beaker, using a small 
quantity of distilled water for rinsing the flask. 

To the solution, which will now contain all of the arsenic in the form 
of arsenate, add 10 to 20 mils of N/2 ammonium chloride solution for every 

1 Apoth. Zeit., 27, 545. 

2 Experience has shown that ten minutes' boiling is not sufficient to remove all of 
the peroxide. Myers and DuMez recommend that after boiling, the last traces of 
peroxide be removed by the addition of a drop or two of permanganate solution (1 per 
cent) and the resulting pink color removed with a slight excess of oxalic acid solution. 

3 Public Health Reports, 1918, 1003. 

4 Sometimes the liquid may still have a pale yellow tint. 

5 Concentration should be effected in such a manner that the formation of sulphuric 
acid fumes in large quantities will be avoided. 



880 ORGANIC SUBSTANCES 

50 mils of the liquid, then 20 mils of magnesia mixture, drop by drop, 
with constant stirring. Finally add an amount of strong ammonia water, 
equal to one-third the volume of the liquid, and 2 mils of alcohol. After 
allowing the mixture to stand for twelve hours, collect the precipitate, 
with the aid of a suction pump, in a Gooch crucible, which has been pre- 
pared as follows: 

Cover the bottom of the crucible with a thin layer of asbestos, which 
has previously been washed with ammonia water (2.5 per cent), and dry 
in an oven at 110° C. Remove the crucible from the oven and place it 
in a larger porcelain crucible, fitted with an asbestos ring so that the sides 
and bottom of the two will not touch, put on the cover and heat slowly 
over an open flame until there is a light-red glow on the outer crucible. 
Remove the Gooch crucible, cool in a desiccator and weigh. 

After the precipitate has been collected, dry the crucible as described 
above, but add a crystal of ammonuim nitrate before heating over the 
open flame. Finally cool the crucible and weigh. The weight of the 
precipitate multiplied by 0.48275 represents the amount of arsenic present 
in the sample taken for analysis, 

Salvarsan in Forensic Testing 

Comparatively large amounts of arsenic can be introduced into the 
body in the form of salvarsan without any symptoms of arsenical poisoning, 
and it is of importance to distinguish between arsenic in this form and 
ordinary inorganic arsenic in cases of suspected arsenical poisoning. 
Positive arsenic reactions are given with the Reinsch, Marsh, and Gutzeit 
tests. Penicillium glaucum gives the garlic odor, but Bettendorf's test 
is negative and hydrogen sulphide gives no precipitate. Ferric chloride 
gives an intense greenish red, auric chloride deep red momentarily; pla- 
tinic chloride is gradually reduced in the cold, Nessler's reagent is reduced 
immediately, and phosphomolybdic acid gives an intense blue. Alpha- 
naphthylamine gives a deep red to violet dye, and the test may be applied 
directly to urine. 

Salvarsan may be recovered unchanged from tissue by extraction with 
alcohol acidified with hydrochloric acid. 

Silver chloride, bromide, and iodide, when freshly prepared, dissolve 
in solutions of arsenobenzene hydrochloride. A solution of silver bromide 
in potassium cyanide is added drop by drop to a solution of the arsenic 
compound until a permanent precipitate is obtained, which is then redis- 
solved by the addition of hydrochloric acid drop by drop. From the solu- 
tion thus obtained sulphuric acid precipitates the arseno-benzene silver 
compound in the form of an insoluble sulphate, which after being washed 



ORGANIC ARSENIC COMPOUNDS 881 

free from the last traces of potassium chloride and cyanide, forms an 
orange to brown powder according to the quantity of silver present. It 
dissolves in water containing a small quantity of sodium carbonate. The 
chlorine compounds possess the least and the bromin the most anti- 
septic power and therapeutic value. 

Dimethylaminotetraminoarsenob enzene 

CH3 CH3 

I I 

NH NH 



NH 2 -/ V-NH2 NH 2 — ( V-NH 





This is a new substance, yellowish green in color, which darkens in 
the air. It is soluble in acetone and acetic acid but only with difficulty 
in alcohol and insoluble in water. 

Arsenoferratin. Sodium Arsenoferrialbuminate 

Arsenoferratin is an arsenic iron albumin compound, obtained by 
introducing the element arsenic into the molecules of ferrialbuminic acid. 
It contains iron in the ferric state equivalent to 6 per cent metallic iron 
and arsenic equivalent to 0.06 per cent as metallic arsenic. It is a brown 
almost odorless and tasteless powder, readily soluble in water and dilute 
alkalies. 

Arsenoferratose is a solution of this substance obtained by dissolving 
5 parts in 68 parts of water with the aid of a little sodium hydroxide, 
20 parts glycerin, 6 parts alcohol, and 1 part Angostura essence. 

For the determination of the iron and arsenic in the solution of Arseno- 
ferratose and applicable also for the salt the following method is recom- 
mended by the laboratory of the American Medical Association. 

Twenty-five mils are evaporated to a viscid consistency in a capacious 
tared crucible and the residue heated in a drying oven at 100° for three 
hours to a constant weight. (The author doubts if it is possible to obtain 
a constant weight by evaporating a mixture containing this quantity 
of glycerin.) The weight of the evaporated residue multiplied by 4 
should be about 23. Now carefully incinerate and ignite. After cooling 
moisten with nitric acid, ignite and finally take up with 10 mils hydro- 
chloric acid. The solution is diluted with 30 mils of water and when cold 



882 ORGANIC SUBSTANCES 

3 grams potassium iodide are added and the mixture allowed to stand for 
an hour in a well-stoppered bottle at the ordinary temperature. It is 
then titrated with N/10 sodium thiosulphate. The iodin liberated should 
require about 12.5 mils of N/10 sodium thiosulphate. 

If arsenoferratose is treated as given below, and the arsenic titrated 
with N/10 iodin solution, the iodin consumed should indicate the pres- 
ence of not less than 0.003 gram arsenic per 100 mils arsenoferratose. 

Fifty mils o£ the arsenoferratose contained in a distillation flask of 
about 500-mils capacity, are heated on a water-bath and evaporated to 
about one-third of its original volume. To the residue are now added 
80 mils of arsenic-free concentrated hydrochloric acid and 20 mils arsenic- 
free 25 per cent solution of ferrous chloride, and the arsenic chloride dis- 
tilled over, the receiver being kept well cooled by means of cold water. 
The contents of the receiver are then supersaturated with sodium bicar- 
bonate, and the arsenic titrated with the N/10 iodin solution. 

Arsen-triferrin 

Arsen-triferrin is an iron arsenoparanucleate containing arsenic in 
organic combination and standardized to contain a definite amount of 
arsenic by diluting with iron paranucleate. It should contain about 16 
per cent of iron, 0.1 per cent of arsenic (As), and 2.5 per cent of phos- 
phorus, all in organic combination. 

Arsen-triferrin is an orange-colored, tasteless powder, soluble in dilute 
alkalies from which it can be precipitated by the addition of an acid. 
It is also soluble in about 8 per cent of hydrochloric acid on warming. 

Arsenic Peptonate 

Arsenic peptonate, for which no definite composition is assigned, is 
prepared by adding a solution of arsenic bromide in strong alcohoKo beef 
peptone suspended in dilute alcohol, and stirring. The finished product 
contains about 45 per cent arsenic figured as AS2O3. 

For assaying this product pour 5 mils concentrated sulphuric acid 
upon 0.2 gram sample in a 200-mil beaker. Heat so that SO3 fumes are 
barely given off, until the liquid becomes clear (cooling and adding more 
sulphuric acid in case the liquid evaporates to less than a layer J inch 
thick before becoming clear). Dilute and neutralize the acid with sodium 
hydroxide. Acidify slightly. Make alkaline with sodium bicarbonate 
and titrate with N/10 iodin. 

Each 0.4046 mil N/10 iodin represents 1 per cent AS2O3. 

If 0.2 gram sample is taken each mil N/10 iodin equals 0.004942 
gram AS2O3. 



ORGANIC ARSENIC COMPOUNDS 883 



Enesol. Mercury Salicylarsenate 

This is a white substance containing 38 to 39 per cent mercury and 
14 to 15 per cent arsenic. It is soluble in water and is employed in syphilis. 

Recently there has been reported x a series of new arsenic compounds 
prepared from a chlorarsenobehenoleic acid or chlorarsenobehenic acid. 
The first reports claimed the latter, but in both cases the strontium salt 
is called "Elarson." The acid is prepared by heating arsenic trichloride 
with behenic or behenoleic acid. It is a brownish-red oil, insoluble in 
water, but dissolving in the alkali solvents and in olive oil. The salts 
resemble soaps. Methyl derivatives have been prepared. 

The new compounds are recommended for secondary anemia, phthisis, 
chorea, neuralgia, and Basedow's disease. 

Elarson contains about 13 per cent arsenic, 6 per cent chlorine and 
9 per cent strontium. It is a white, amorphous, tasteless powder, insolu- 
ble in water, but slightly soluble in alcohol and ether. 

Elarson is broken up by boiling with alcoholic potash under a reflux. 
If the alcoholic liquid is diluted, a portion of the solution on treatment with 
dilute sulphuric acid and filtered, will give characteristic tests for arsenic 
and chloride. The balance of the solution, diluted with water, acidified 
with dilute hydrochloric acid and filtered, will yield a precipitate of stron- 
tium oxalate on treatment with ammonia and ammonium oxalate. 

1 Forshn. Therap. d. Gegenw., 54, 1. Am. 403, 106. 



CHAPTER XXIII 
PROTEINS AND DIGESTIVES 

PROTEINS 

The chemistry of the proteins in so far as it affects the drug analyst 
is confined to those groups which occur in beef and vegetable extracts, 
predigested meat products, extracts of fish livers, casein, and nucleic acid 
preparations. A detailed account and description of all of the different 
classes of proteins is not essential in a work of this kind, but a brief sum- 
mary of the characteristics of the important groups will enable the chemist 
to comprehend the" fundamental status of protein chemistry. 

Accompanying the proteins in beef are the xanthin derivatives, creatin 
and creatinin. These nitrogenous substances, though they are not pro- 
teins, are always important factors in studying meat and vegetable extracts. 
The xanthin bases have been described in the section on Alkaloids. 

S. B. Schryver in the new edition of Allen, Vol. 8, p. 17 et seq., gives 
a very comprehensive resume of the chemistry of the proteins. He classi- 
fies the proteins as follows: Simple proteins, conjugated proteins, and 
derived proteins. The first class include the protamines, highly nitro- 
genous substances; histones, also containing considerable nitrogen; 
albumins, water-soluble proteins of egg white and blood serum; globulins, 
insoluble in water and widely distributed; prolamines, soluble in 70 to 90 
per cent alcohol, gliadin being an example; glutenins; scleroproteins or 
albuminoids. The second class include the nucleoproteins; glycopro- 
teins; phosphoproteins ; hemoglobins, and lecitho proteins. The last 
class include the metaproteins obtained by acid and alkaline digestion 
of the proteins; proteoses, peptones, and polypeptides derived by the 
action of enzymes and the latter also by synthesis. 

The proteins differ from one another in the number and kind of amino 
acids which they yield on hydrolysis. They are formed by the conden- 
sation of several amino acids according to the scheme: 

R 1 R 11 R m 

I 
i 






NH 2 — CH— CO OH HNHCH— COOH HNHCH— CO OH HNH 



R N 



—COOH H PI— 

884 



PROTEINS AND DIGESTIVES 885 

The hydrolytic products of the proteins thus far isolated and identified 
include about a score of amino acids, the simplest being glycine or amino- 
acetic acid, (NH 2 )CH 2 COOH. Others thus far identified are: 

Alanine, alpha-aminopropionic acid, CH3CH(NH)2COOH. 

CH3. 
Valine, alpha-aminoisovaleric acid, yCH • CH(NH 2 )COOH. 

CH 3 
CH3. 
Leucine, alpha-aminoisocaproic acid, yCK • CH 2 • CH(NH 2 )COOH. 

CH 3 
Isoleucine, alpha-amino-beta-methyl-beta-ethyl propionic acid. 

CH3 \ 

>CH-CH(NH 2 )COOH 

C 2 H 5 / 

Phenylalanine, beta-phenyl-alpha-amino propionic acid, 

C 6 H 5 CH 2 CH(NH 2 )COOH 

Serine, beta-hydroxy-alpha-aminopropionic acid, 

OHCH 2 CH(NH 2 )COOH 

Cystine, Di-beta-thio-alpha-aminopropionic acid, 

HOOC • CH(NH 2 ) • CH 2 S— S • CH 2 • CH(NH 2 )COOH 

Aspartic or aminosuccinic acid, HOOC CH 2 CH(NH 2 ) COOH. 
Glutamic or alpha-aminoglutaric acid, 

HOOC • CH 2 ■ CH 2 • CH(NH 2 ) • COOH 
Arginine, alpha-amino-delta-guanidine valeric acid, 

NH 2 

/ 
NH=C — CH 2 • CH 2 • CH 2 • CH(NH 2 ) ■ COOH 

\ / 
NH 

Lysine, alpha-epsilon-diaminocaproic acid, 

H 2 N • CH 2 • CH 2 • CH 2 • CH 2 • CH(NH 2 ) • COOH 

Caseinic or diaminotrihydroxydodecanic acid, Ci 2 H 2 gOsN 2 . 
Histidine, beta-iminazole-alpha-aminopropionic acid, 

CH 

/ \ 
N NH 

/ \ 

HC==C— CH 2 • CH(NH) 2 • COOH . 



886 ORGANIC SUBSTANCES 

Proline, alpha-pyrrolidine carboxylic acid, 

CH2 == CH2 

I I 

CH 2 CHCOOH 

\ / 
NH 

Hydroxyproline, hydroxy pyrrolidine carboxylic acid, C5H6O3N. 
Trytophan, beta-indole-alpha-aminopropionic acid, 

C— CH 2 • CH • (NH 2 ) • COOH 

/ \ 
CeHi CH 

\ / 
NH 

The vegetable proteins belong to the albumins, globulins, glutelins, 
and prolamines, no representative of the remaining groups having been 
found. 

Qualitative Reactions of Proteins. — Nitrogen and sulphur are present 
in proteins and may be recognized by the usual methods of detecting 
them in organic combination. Some water-soluble proteins coagulate 
on heating and others require the presence of a little acid. Strong alco- 
holic solutions usually precipitate. Concentrated nitric acid causes a 
precipitate with proteins, and potassium ferrocyanide added to a solution 
distinctly acid with acetic acid produces a white flocculent precipitate. 
Some of the alkaloidal reagents, notably phosphotungstic and phosphomo- 
lybdic acids, Mayer's reagent, potassium-bismuth iodide, tannic and 
picric acid, yield precipitates. 

The derived proteins, especially the proteoses and peptones, are not 
affected by the majority of the precipitating reagents. Gelatin does not 
precipitate with ferrocyanide. 

Aqueous solutions of proteins give, with Millon's reagent (a freshly 
prepared solution of mercurous nitrate with nitrous acid in solution), 
a white precipitate which turns brick-red on boiling, and the supernatant 
liquid becomes red after standing. Solid proteins turn red on boiling 
with the reagent. Sodium chloride must be absent when this test is 
performed. 

Another important color reaction is the biuret test, which is obtained 
when a solution of an albumin or globulin is treated with a few drops of 
a very dilute solution of copper sulphate followed by a slight excess of 
fixed alkali. The blue precipitate formed by the copper will dissolve 
with the production of a violet color. With certain proteoses a reddish 
or rose color is obtained. 



PROTEINS AND DIGESTIVES 887 

MEAT PRODUCTS 
Beef Extract 

Beef Extract is a product obtained by extracting fresh meat with 
boiling water and concentrating the liquid portion by evaporation, after 
the removal of the fat. Sodium chloride is generally added, and the 
finished extract is of semi-solid or pasty consistency. It should contain 
not less than 75 per cent of total solids, nor over 27 per cent of ash, not 
over 12 per cent sodium chloride, not over 0.6 per cent of fat and not less 
than 7 per cent of nitrogen. 

Fluid meat extract has the same characteristic ingredients, but is 
concentrated to a lower degree. 

Good meat extract contains no albumin. 

Creatin is constantly present in flesh, creatinin, its dehydrated form, 
occurs to some extent in flesh and in larger amount in meat extracts. 
These two substances are therefore characteristic components of meat 
extracts. 

/NH 2 
Creatin, NH : C< 

X N(CH3)CH 2 

/NH— CO 
Creatinin, NH : C< \ 

X N(CH 3 )CH 2 

Meat extract contains the following substances: 

Non-nitrogenous Extractives. Nitrogenous Extractives. 

Glycogen Creatin 

Dextrin and Sugars Creatinin 

Lactic acid Xanthin 

Inositol Hypoxanthin 

Uric Acid 

Urea 

Carnin 

Inositic acid 

Taurin 

Methods of Analysis of Meat Extracts. — The methods given are those 
of the Association of Official Agricultural Chemists 1 and were developed 
and adapted to this class of products by F. C. Cook. 

The liquid and semi-liquid extracts should be removed from the con- 
tainer and mixed before sampling. Warming will expedite the mixing 
of pasty extracts. Liquid preparations often show a sediment and this 
should be carefully removed and mixed with the sample. If the sample 
is in the form of cubes, 10-12 units should be ground. 
1 Jour. A. O. A. C, 1, 1915-1916, 280. 



888 ORGANIC SUBSTANCES 

Moisture. — Use 2 grams of powdered preparations,. 3 grams of pastes 
and 5 to 10 grams of liquids. Dissolve the pasty preparation in water 
and dry with sufficient ignited sand, asbestos, or pumice to absorb the 
solution. The determination is made in a vacuum drying-oven at the 
temperature of boiling water, or in the open in a current of hydrogen. 
The moisture is usually expelled in five hours. 

Ash. — Char a quantity of the substance, representing about 2 grams 
of the dry material, and burn at a low heat, not to exceed dull redness, 
until free from carbon. If a carbon-free ash does not result, exhaust the 
charred mass with hot water, collect the insoluble residue on a filter, 
burn till the ash is white or nearly so, and then add the filtrate to the ash 
and evaporate to dryness. Heat to low redness till the ash is white or 
grayish white and weigh. 

Total Phosphorus. — Use 2 to 2.5 grams of a solid or paste and an equiva- 
lent quantity of a liquid preparation. Digest in a Kjeldahl flask with 
concentrated sulphuric acid and potassium sulphate. After the solution 
becomes colorless, cool, add 100 mils of water and boil for a few minutes. 
Neutralize with ammonia, cool, and precipitate with magnesia mixture. 
After standing with an excess of ammonia, this crude precipitate is then 
to be filtered off, washed with dilute ammonia, dissolved in dilute nitric 
acid and precipitated with ammonium molybdate. The balance of the 
determination follows the usual course of a phosphate analysis. 

Chlorine. — Dissolve about 1 gram of the sample, prepared as directed 
above in 20 mils of 5 per cent sodium carbonate, evaporate to dryness, 
and ignite as thoroughly as possible at a temperature not to exceed dull 
redness. Extract with hot water, filter, and wash. Return the residue 
to the platinum dish and ignite to an ash; dissolve in sufficient nitric 
acid (1 in 10), add this solution to the water extract. Add a known volume 
of N/10 silver nitrate in slight excess, stir well, filter, and wash thoroughly. 
To the filtrate and washings add 5 mils of saturated solution of ferric 
alum and a few mils of dilute nitric acid. Titrate the excess of silver 
with N/10 ammonium or potassium thiocyanate until a permanent light- 
brown color appears. 

Fat. — Transfer the residue from the determination of moisture to a 
continuous extraction apparatus and extract with anhydrous ether for 
sixteen hours. Dry the extract at the temperature of boiling water for 
thirty minutes, cool in a desiccator, weigh; continue at thirty-minute 
intervals, this alternate drying and weighing to constant weight. 

Total Nitrogen. Gunning Method. — Place .7 to 3.5 grams, according 
to the nitrogen content, of the substance to be analyzed in a digestion 
flask (Pyrex type, 500-mil capacity). Add 10 grams powdered potassium 
sulphate and 15 to 25 mils concentrated sulphuric acid (.1 to .3 gram 
crystallized copper sulphate also may be added). Place the flask in an 



PROTEINS AND DIGESTIVES 889 

inclined position and heat below the boiling-point until frothing ceases. 
Digest for a time after the mixture is colorless or nearly so, or until oxida- 
tion is complete. Cool, dilute with about 200 mils of water, add a few 
pieces of granulated zinc or pumice stone, if necessary to prevent bumping, 
a little phenolphthalein, and sufficient strong sodium hydroxide solution 
to make the reaction strongly alkaline. Connect the flask with a con- 
denser, using a rubber stopper through which passes the lower end of a 
Kjeldahl connecting bulb, and distill until all the ammonia has passed 
over into a measured quantity of standard acid (N/2 is usually the best 
strength to employ) and titrate with standard alkali. The first 150 mils 
of distillate will generally contain all of the ammonia. Before receiving 
the distillate in the acid, the latter should be treated with a few drops 
of methyl red, which is the indicator to be used for this titration. 

1 mil of N/1 acid = .01703 gram NH 3 

1 mil of N/1 acid = .014 gram N 

1 mil of N/2 acid = .008515 gram NH 3 

Nitrogen X6.25 = Protein (Meat, Food and Feeding Stuffs) 

Nitrogen X 6.38 = Casein and Albumin 

Nitrogen X 5.7 = Wheat Protein. 

Insoluble Protein. — Dissolve 5 grams of powdered preparations, 8 to 10 
grams of pasty extracts, or 20 to 25 grams of fluid extracts in cold water. 
Filter and wash with cold water. Transfer the filter and contents to a 
Kjeldahl flask and determine the nitrogen as directed above. However, 
if a large amount of insoluble matter is present, transfer the weighed sample 
to a graduated flask, make up to a definite volume, shake thoroughly, 
filter through a dry folded filter, and determine the nitrogen in an aliquot 
of the filtrate. Deduct the percentage of nitrogen in the total filtrate 
from the percentage of total nitrogen to obtain the percentage of nitrogen 
in the insoluble protein. Multiply this percentage by 6.25 to obtain 
percentage of insoluble protein. 

Coagulable Protein. — Prepare a solution of the sample as directed 
above. Employ as large an aliquot of the filtrate as practicable, neu- 
tralize to phenolphthalein by the addition of acetic acid or sodium hydrox- 
ide, whichever may be necessary, add 1 mil N/l acetic acid, boil for 
two to three minutes, cool to room temperature, dilute to 500 mils and 
pass through a dry folded filter. Determine nitrogen in 50 mils of the 
filtrate. Ten times the percentage of nitrogen so obtained, subtracted 
from the percentage of soluble nitrogen (total nitrogen minus the per- 
centage of nitrogen occurring as insoluble protein) gives the percentage 
of nitrogen present as coagulable protein. Multiply this figure by 6.25 
to obtain the percentage of coagulable protein in the sample. 



890 



ORGANIC SUBSTANCES 



Proteoses, Peptones and Gelatin. — Modified Tannin-Salt Method. — 
Use the filtrate obtained in the estimation of coagulable proteins. Trans- 
fer a 50-mil aliquot to a 100-mil graduated flask, add 15 grams sodium 
chloride and 10 mils of cold water, shake until the sodium chloride has 
dissolved and cool to 12° C. Add 30 mils of 24 per cent tannin solution, 
cooled to 12° C, fill to mark with water previously cooled to 12° C, shake 
and allow the mixture to stand at a temperature of 12° C. for twelve 
hours or overnight. Filter at 12° C. through a dry filter, transfer 50 mils 
of the filtrate to a Kjeldahl flask and add a few drops of sulphuric acid. 
Place the flask in a steam-bath, connect with a vacuum pump and evapo- 
rate to dryness. Determine the nitrogen in the residue. Conduct a 
blank determination, using the same amount of reagents and correct the 
result accordingly. Multiply the corrected result by 2 and deduct the 
amount of nitrogen as found from the amount of nitrogen determined 
in another 50-mil aliquot of the filtrate from the coagulable proteins 
without the tannin-salt treatment; the difference multiplied by 6.25 gives 
the percentage of proteoses, peptones and gelatin. 

Meat Bases. — Deduct from the percentage of total nitrogen the sum 
of the percentages of nitrogen obtained in the determination of insoluble 
proteins, coagulable proteins, and proteoses, peptones and gelatin, to 
obtain the percentages of nitrogen in the meat bases. Multiply the result 
by 3.12 to obtain the percentages of meat bases. 

Ammonia. Folin Method. — Employ the apparatus shown below. A 
is a wash bottle one-quarter full of 10 per cent sulphuric acid; B is a tube 




containing the sample; C is a rubber disk and D is a 5-mil spray bulb 
to prevent spray from being carried over in the tube E, which contains 
the standard acid; F is a safety bottle. 



PROTEINS AND DIGESTIVES 891 

Mix 1 gram of the meat extract with 2 mils N/l hydrochloric acid, 
wash into tube B with about 5 mils of ammonia free water. Place a 
measured amount of N/25 or N/50 sulphuric acid or hydrochloric acid in 
tube E. Then add 1 mil of saturated potassium oxalate solution to the 
sample in tube B, introduce a few drops of kerosene and finally add just 
sufficient saturated potassium carbonate solution to render the mixture 
alkaline. Place the tubes in position at once, pass air through the appa- 
ratus and titrate the standard acid in tube E at hourly intervals, until 
ammonia ceases to be given off, using methyl red as indicator. 

Proteoses and Gelatin. — Use the filtrate obtained in the estimation of 
coagulable protein. Evaporate to small volume and saturate with zinc 
sulphate (about 85 grams to 50 mils, avoiding such an excess as would 
later cause bumping). Let stand several hours, filter and wash the pre- 
cipitate with saturated zinc sulphate solution, place the filter and pre- 
cipitate in a Kjeldahl flask and determine the nitrogen. Or, if the pre- 
cipitate is voluminous, make up to a definite volmne with saturated zinc 
sulphate solution, filter and determine the nitrogen in an aliquot of the 
filtrate. Subtract the nitrogen thus obtained from the nitrogen in the 
filtrate from the coagulable protein to obtain the nitrogen of the pre- 
cipitated protein (proteoses and gelatin). 

Acid Alcohol-soluble Nitrogen. — Transfer 10 mils of an aqueous solu- 
tion of the sample (10 grams dissolved in sufficient water to make 100 
mils) or, if the sample is insoluble in water, 1 gram and 10 mils of water, 
to a 200-mil glass-stoppered measuring cylinder, add 1.2 mils of 12 per 
cent hydrochloric acid, mix and add absolute alcohol to the 200-mil 
mark. Mix thoroughly and set aside for several hours. Filter off a 100- 
mil aliquot, evaporate alcohol and determine nitrogen in the residue. 

Creatin. — Dissolve about 7 grams of the sample in cold (20° C.) 
ammonia-free water in a 150-mil beaker, transfer the solution to a 250- 
mil measuring flask, dilute to the mark and mix thoroughly. Transfer 
a 20-mil aliquot of this solution to a 50-mil measuring flask, add 10 mils 
2/N hydrochloric acid and mix. Hydrolyze in an autoclave at 117 to 
120° C. for twenty minutes, allow the flask to cool somewhat, remove 
and chill under running water. Partially neutralize the excess of acid 
by adding 7.5 mils of 10 per cent sodium hydroxide solution free from 
carbonates, dilute to mark and mix. Make a preliminary reading on 
20 mils to ascertain the volume to use to obtain a reading of approxi- 
mately 8 mm. and transfer to a 500-mil graduated flask. Add 10 mils 
of 10 per cent hydroxide solution and 30 mils saturated picric acid solu- 
tion. Mix and rotate for thirty seconds and let stand exactly 4| minutes. 
Dilute to the mark at once with water, shake thoroughly and read in a 
Duboscq colorimeter, comparing the color with N/2 potassium dichromate 
set at 8 mm. 



892 ORGANIC SUBSTANCES 

If the reading is too high or too low (above 9.5 or below 7 mm.), cal- 
culate the quantity necessary to obtain a reading of about 8 mm. The 
strength of the dichromate solution used must be checked against a 
standard creatin solution. To obtain the values, divide 81 by the reading 
and multiply by the volume factor to obtain milligrams of creatinin; sub- 
tract from the combined creatinin value the equivalent of the pre-f ormed 
creatinin (determined below); this value Xl.16 gives creatin, which, 
divided by the weight of the sample and multiplied by 100 gives the per 
cent of creatin. 

Creatinin. — Measure about 5 mils of the solution employed above 
into a 500-mil measuring flask, add 10 mils of 10 per cent sodium hydroxide 
solution and 30 mils of saturated picric acid solution, mix and rotate 
for thirty seconds. Allow to stand exactly 4| minutes, then dilute to the 
mark at once with water. Shake thoroughly and read the depth of color 
after standing. If the reading is less than 7 or over 9.5 mm., repeat, 
calculating the quantity of solution necessary to obtain a reading of 
about 8 mm. Express the results as per cent of creatinin, making the 
calculations as indicated above. 

Nitrates. Phenoldisulphonic Acid Method. — Reagents. Phenoldisul- 
phonic Acid Solution. — Heat 6 grams of phenol with 37 mils of concen- 
trated sulphuric acid on a water-bath, cool, and add 3 mils of water. 

Standard Comparison Solution. — Dissolve 1 gram of pure dry potas- 
sium nitrate in water and dilute to 1 liter. Evaporate 10 mils of this 
solution to dryness on a steam-bath, add 2 mils of the phenoldisulphonic 
acid solution, mix quickly and thoroughly by means of a glass rod, heat 
for about one minute in a steam-bath and dilute to 100 mils. One mil 
of this solution is equivalent to .1 mg. of potassium nitrate. Prepare a 
series of standard comparison tubes by introducing amounts ranging from 
1 to 20 mils of this solution (.1 to 2 mg. of KNO3) into 50-mil Nessler 
tubes, adding 5 mils of strong ammonium hydroxide and diluting to 50 
mils. These standard tubes are permanent several weeks if kept 
tightly stoppered. 

Determination. — Weigh 1 gram of the sample if a solid or 10 mils if 
liquid, into a 100-mil flask, add 20 to 30 mils of water and heat on a steam- 
bath for fifteen minutes, shaking occasionally. Add 3 mils of saturated 
silver sulphate solution for each per cent of sodium chloride present, then 
10 mils of basic lead acetate solution and 5 mils of alumina cream, shaking 
after each addition. Make up to the mark with water, shake and filter 
through a folded filter, returning the filtrate to the filter until it runs 
through clear. Evaporate 25 mils of the filtrate to dryness, add 1 mil 
of the phenol disulphonic acid solution, mix quickly and thoroughly by 
means of a glass rod, add 1 mil of water and 3 to 4 drops of concentrated 
sulphuric acid and heat on a steam-bath for two to three minutes, being 



PROTEINS AND DIGESTIVES 893 

careful not to char the material. Then add about 25 mils of water and 
an excess of ammonium hydroxide, transfer to a 100-mil graduated flask, 
add 1 to 2 mils of alumina cream if not perfectly clear, dilute to the mark 
with water and filter. Fill a 50-mil Nessler tube to the mark with the 
filtrate and determine the amount of potassium nitrate present in the 
sample by comparison with the standard comparison tubes. If the 
solution is too dark for comparison with the standards, dilute with water 
and correct the result accordingly. 
Glycerin. See pages 548-549. 

Yeast Extract 

Yeast on hydrolysis yields extractives similar to those obtained from 
meat. The water extract on evaporation darkens and acquires an odor 
similar to beef extract, and on superficial examination the two products 
appear identical. Yeast extract contains no creatin or creatinin while 
in a typical meat extract from 10 to 20 per cent of the total nitrogen is 
present in the form of these bodies. The distribution of the xanthin 
bases differs in meat extracts, xanthin, and hypoxanthin predominate 
while in yeast extracts adenin and guanin predominate. The most impor- 
tant test for determining the nature of the extract is the estimation of 
the creatin and creatinin. The analytical methods of the A. O. A. C. 
for meat extracts are applicable to yeast extracts. 

Beef Peptone 

Beef peptone is usually prepared by digesting lean beef with pine- 
apple juce in a steam-jacketed boiler with a mechanical stirrer. When 
the beef is digested the liquid is strained and concentrated in vacuo to 
a thick syrup, dried, and pulverized. The product is often sold as Beef 
Meal and is sometimes mixed with cacao and sugar. 

Beef Jelly 

Beef jelly is prepared by mixing 50 parts of beef peptone, with 43 
parts beef extract and 7 parts of sodium chloride. 

Beef, Iron, and Wine 

Beef, Iron, and Wine is a liquid preparation consisting of extract of 
beef or beef peptone dissolved in an hydro alcoholic solution (wine) with 
the aid of sodium or ammonium citrate and accompanied by iron chloride. 
Cinchona alkaloids, digestives, coca, and other drugs are often added to 
the formula. 



894 ORGANIC SUBSTANCES 

The actual medicinal content of this class of preparations vanished 
to such an alarming extent at one time that the Bureau of Internal Revenue 
ruled that a special tax must be paid for the sale of any product having 
a protein content lower than 1.4 per cent. This value is a minimum 
for the average product made according to the National Formulary. 

Cod-liver extracts when made from fresh livers probably contain some 
of the proteins occurring in beef extract. If made from putrid livers a 
number of simpler amines such as butylamine, amylamine, asellin, mor- 
rhuine, will be found. These extracts are also combined with wine 
beef extract, beef peptone, hypophosphites, creosote, iron chloride, and 
citrates. 

Ruddirnan and Kebler, 1 from a critical study of Beef, Iron, and Wine 
made according to the National Formulary, conclude that the product 
should possess the following characteristics: 50 mils when assayed by 
the Gunning method for total nitrogen should yield not less than . 10 gram 
of nitrogen coming from the beef extract. If the amount of nitrogen 
obtained by the barium carbonate method exceeds .006 gram the excess 
is to be considered as coming from an ammonium compound and is to 
be deducted from the total nitrogen obtained, the remainder representing 
the nitrogen coming from the beef extract. Fifty mils should contain 
not less than .07 gram nor more than .08 gram of iron calculated as 
metallic iron. The percentage of alcohol should not be under 14 nor 
over 20. 

The nitrogen determination is complicated when ammonium salts 
are present. The National Formulary preparation calls for sodium 
citrate, but many proprietary preparations are made up with ammonium 
citrate. Some workers determine the total nitrogen by the Gunning 
procedure, and then estimate the ammoniacal nitrogen in another sample 
by distillation with magnesium oxide, the difference between the figures 
obtained representing the percentage of nitrogen as beef extract. 

Ruddirnan and Kebler believe that magnesium oxide liberates some 
of the ammonia from nitrogenous constituents of the beef extract and 
recommend distillation with barium carbonate. Fifty mils of the sample 
in a 500-mil Kjeldahl flask are treated with 200 mils of water,. 3 grams 
of barium carbonate, and a few pieces of granulated zinc or pumice. The 
flask is connected with the condenser in the usual way and the distillate 
received in N/10 acid. The ammonia liberated is considered as coming 
from added ammonium salts. 

The developement of Folin's aeration method for ammonia pre- 
viously described under meat extracts took place subsequent to the 
researches of Kebler and Ruddirnan and is probably applicable to the 
Beef, Iron, and Wine products. 

1 U. S. Dept. Agri., Bu. Chem. Bull., 137, p. 194. 



I 



PROTEINS AND DIGESTIVES 895' 

Nucleoproteins. Phosphoproteins 

The nucleic acid of yeast is used therapeutically in combination with 
some of the heavy metals. The solutions of the compounds are usually 
antiseptic and non-irritant. The silver compound is known as Nargol 
and Argentose, the mercury compound is called Mercurol and the copper 
compound Cuprol. 

Nucleic acid and nucleoproteins contain phosphorus in organic com- 
bination. They are distinguished from phosphoproteins by the fact that 
the latter on treatment with 1 per cent sodium hydroxide at 37° undergo 
hydrolysis and yield their phosphorus in the form of phosphoric acid 
which can be directly precipitated with ammonium magnesium chloride, 
whereas the phosphorus of nucleoproteins remains in organic combination 
when subjected to the same treatment. 

Nucleic acids yield a number of substances on hydrolysis with acids; 
the purine bases guanin, adenin, xanthin, and hypoxanthin, cytosin, 
uracil, and thymin. derivatives of pyrimidin; carbohydrates and their 
degradation products, formic and levulinic acids; and phosphoric acid. 

Casein and Vitellin 

Special preparations of casein are used as concentrated foods for 
diabetic patients, neurasthenics, and convalescents. They are often com- 
bined with glycerophosphates, and the casein is rendered soluble by 
sodium bicarbonate, sodium citrate, sodium or potassium phosphate, etc. 
Products of the Sanatogen, Eulactol, Plasmon, Nutrose and Sanose types 
fall in this class. Argonin is a soluble silver casein compound which 
furnishes a non-irritant antiseptic useful in venereal diseases. 

Casein compounds are very useful as a means of administering other 
medicinal agents such as lithium, mercury, silver, iron, arsenic, alkaloids, 
salicylates, etc. 

The nomenculature in relation to casein is confusing. Casein or free 
casein is the base-free or uncombined protein; calcium casein or caseinate 
is the neutral compound that is believed to be present in fresh normal 
milk, the CaO being present to the amount of 1.50 per cent; basic calcium 
casein or caseinate is the compound consisting of casein with 2.50 per 
cent CaO; calcium paracasein or paracaseinate is the insoluble compound 
formed by the action of rennet on calcium casein; paracasein or free 
paracasein is the base free or uncombined protein. 

Free casein may be separated from milk or its soluble compounds by 
precipitating with acetic or mineral acids. 

The amount of casein is obtained by determining the nitrogen by the 
Kjeldahl-Gunning method and multiplying by 6.38. 

Casein is a phosphoprotein. This class of substances is distinguished 



896 ORGANIC SUBSTANCES 

from others by the fact that on treatment with 1 per cent sodium hydroxide 
at 37° for twenty-four to forty-eight hours the whole of the phosphoric 
acid is set free from organic combination. 

Vitellin 

Vitellin in combination with silver is known as Argyrol. Vitellin is 
a phosphoprotein of acid character which is obtained as a white granular 
residue on extracting egg yolk with large quantities of ether. It is soluble 
in saturated sodium chloride, and reprecipitated on adding an excess of 
water. 

DIGESTIVES 

The digestive ferments occupy a prominent place among modern 
remedial agents. The conditions under which the different ferments 
act are usually dissimilar; pepsin, for instance, develops its greatest 
digestive power at a temperature of 40° C. and in a weak acid medium, 
while the properties of diastase show to the best advantage in a neutral 
medium. While it was formerly held that a mixture of ferments could 
be counted upon to be active only with respect to one of the ingredients, 
it now appears that the value of these mixtures can be attributed to all 
of their components. 

The commercial ferments are extractive preparations containing the 
enzymes which bring about the transformation of foods in the plants 
or animals containing them. 

Proficiency in assaying digestive preparations and interpreting the 
results obtained can be acquired only with considerable practice. The 
results are always comparative, and the dynamics of the reactions are 
perhaps more closely connected with physiological chemistry than with 
those answering the laws of stable elements and compounds. Many 
factors influence the manipulations. Degrees of concentration should be 
taken into consideration. In all cases it is good practice to run parallel 
tests with standard products of known potency. In endeavoring to check 
claims of digesting value advanced on the label or in the literature of an 
individual product, due regard must be taken of the fact that for a long 
time the laboratory of every firm had its own methods of testing, and 
the claims were based on the results of assays by these methods. 

The Proteoclastic Enzymes 

The chief commercial preparations of this class are pepsin, pancreatin, 
and papain. 

Pepsin 

Pepsin is obtained from the mucous membrane of the stomach of the 
hog, and when purified the commercial product is a yellowish-white scale 



PROTEINS AND DIGESTIVES 897 

or amorphous powder, consisting of albuminous material with varying 
amounts of the ferment. 

Pepsin is dispensed in liquid and solid form. The nqmds are usually 
elixirs, syrups, or wines, and are prepared with saccharated pepsin. The 
combinations include bismuth and ammonium citrate, ferric pyrophos- 
phate, extract of cinchona, strychin, gentian, beef peptone, and occasion- 
ally other drugs. Pancreatin and other digestives are sometimes com- 
bined with pepsin. 

Lactated pepsin is a mixture of pepsin, pancreatin, diastase, and 
maltose, with hydrochloric and lactic acids. This same combination 
with aromatic powder is sold in tablet form. 

Digestive powders contain pepsin, pancreatin, bismuth subcarbonate, 
and aromatics. In tablets and pills pepsin will be found in combination 
with one or more of the other digestives, bismuth salts, gentian, charcoal, 
sodium bicarbonate, Nux Vomica, caffein, antipyretic drugs, Capsicum, 
ipecac, ginger, cerium oxalate, inspissated ox gall, salol, and cinchona 
alkaloids. 

Pepsin is an ingredient of chewing gums. The products sold at the 
present time actually contain detectable quantities of pepsin, which was 
not the case before the activities of control legislation. 

Quantitative determinations of pepsin are actually measures of the 
digestive power of the particular specimen under examination. Two 
specimens of the same appearance and weight may possess totally different 
potencies. The pepsin of the U. S. standard is 1-3000, which means that 
one part of pepsin will digest 3000 times its weight of specially prepared 
egg albumin at a specified temperature and within a specified period. 
There are no standards for products containing pepsin, and there is no 
way of actually measuring the quantity of pepsin present, unless a decla- 
ration on the label indicates that a certain amount of pepsin of a definite 
potency has been used. In the latter case a measure of the digesting 
power will furnish an approximate idea of the quantity used. Prepara- 
tions containing pepsin, especially those of liquid nature, are subject to 
fairly rapid deterioration, and while they may be potent as remedial 
agents when freshly made, they will often be inert after a few months 
or even weeks unless preserved under special rigid conditions which are 
generally impracticable from a commercial and household standpoint. 

Determination of Proteolytic Activity 

U. S. P. Method for Pepsin. — Mix 25 mils of normal hydrochloric 
acid V. S. with 275 mils of distilled water and dissolve .1 gram of pepsin 
in 150 mils of this liquid. Immerse a hen's egg, which is not less than 
five nor more than twelve days old and has been kept in a cool place, in 
boiling water during fifteen minutes. As soon as the egg has sufficiently 



898 ORGANIC SUBSTANCES 

cooled to handle it, remove the pellicle and all of the yolk; at once rub, 
the albumen through a clean, dry hair or brass, No. 40, sieve, reject the 
first portion that passes through the sieve, and place 10 grams of the suc- 
ceeding portion in a wide-mouthed bottle of 100 mils' capacity. Immedi- 
ately add 2 mils of the acid liquid and, with the aid of a rubber-tipped 
glass rod, moisten the albumen uniformly. Again add 2 mils of the acid 
liquid, repeat the manipulation with the glass rod, and with gradually 
increasing portions of the acid liquid, until the total amount added 
measures 20 mils. Thoroughly separate the particles of albumen from 
each other, rinse the rod with 15 mils more of the acid liquid, and, after 
warming the mixture to 52° C, add exactly 5 mils of the solution of pep- 
sin. At once cork the bottle securely, invert it three times, and place 
it in a water-bath that has previously been regulated to maintain a temper- 
ature of 52° C. Keep it at this temperature for two and one-half hours, 
agitating the contents every ten minutes by inverting the bottle once. 
Then remove it from the water-bath, pour the contents into a conical 
measure having a diameter not exceeding 1 cm. at the bottom, and trans- 
fer the undigested egg albumen which adheres to the sides of the bottle 
to the measure with the aid of small portions (about 15 mils at a time) 
of distilled water, until the total amount used measures 50 mils. Stir 
the mixture well and let it stand for half an hour; the deposit of undis- 
solved albumen does not then measure more than 1 mil. 

The relative proteolytic power of pepsin, stronger or weaker than 
that just described, may be determined by ascertaining through repeated 
trials the quantity of the pepsin solution, made as directed in the assay, 
required to digest, under the prescribed conditions, 10 grams of boiled 
and disintegrated egg albumen. Divide 15,000 by this quantity expressed 
in mils to ascertain how many parts of egg albumen one part of Pepsin 
will digest. 

Method for Liquid Pepsin. — Chestnut has developed a method for 
determining proteolytic activity which in skilled hands has given excellent 
results. 

Preparation of Sample. — Add to 50 mils of the liquid under exami- 
nation the requisite quantity of either N/10 HC1 or H2O or both, to make 
the preparation of N/10 acid strength when diluted with N/10 HC1 to 
90 mils. Preserve the sample in a refrigerator. 

Preparation of Reagents. 1. Standard Pepsin. — Powder a good grade 
of acid soluble U. S. P. pepsin and pass it through a No. 60 sieve; dry 
in vacuo over H2SO4, pass again through a sieve and preserve in a stop- 
pered bottle over H2SO4.' The exact pepsin equivalent of the dry powder 
must be ascertained by the U. S. P. process, and this may be expressed 
in percentage based on the supposition that the U. S. P. product is 100 
per cent pure. 



PROTEINS AND DIGESTIVES 899 

2. Pepsin Solutions. — Weigh off definite amounts of the standard 
pepsin from a weighing tube into the requisite quantity of N/10 HO to 
make, 

2a: A 1 per cent solution. 
26: A .1 per cent solution. 

These should be freshly prepared, since weak solutions of pepsin in 
N/10 HC1 suffer decomposition on standing . 

3. Add 1 mil of N/10 HC1 to 9 mils of the sample. 

3a. Immerse a stoppered flask containing 45 mils of the sample and 
5 mils of N/10 HO in boiling water for fifteen minutes and filter. 

36. Immerse a stoppered test-tube containing 18 mils of solution 3 
in boiling water for ten minutes, and after cooling, add 2 mils of solution 
2a, and filter if necessary. 

4. Ricin Solution. — The cheap commercial " Ricin Praparatnach 
Jacoby " manufactured in Germany is ground to a No. 60 powder, 
thoroughly mixed and dried, and then stored in a desiccator. Digest 1 
gram of this powder for one hour at 37.5° C. in 100 mils of 5 per cent of 
Nad solution, cool and filter. 

Method. — To each of fifteen tubes first add. from a burette, 2 mils of 
the ricin solution and a half mil of N/10 HO. Heat to 37.5° C. and 
then add the quantities of solutions Nos. 26, 3, 3a and 36, indicated in 
the following tables. Measure off solutions 3a first and then pour in the 
solutions to be tested as rapidly as possible from graduated pipettes, 
taking note of the total time consumed in the process and beginning first 
with tube No. 1 and then following in natural sequence. 

Sample Tables 

No. of tubes 1 2 

No. of mils 3 added 0. .25 

No. of mils 3a added 1 . .75 

Time of digestion in minutes . No 

digestion 68 42 28 19 

Series II 

No of tubes 1 2 

No of mils 3a added 1 . .75 

No. of mils 36 added 0. .25 

Time of digestion in minutes . . Xo 

digestion 68 42 28 19 

Series III 

No. of tubes 1 2 

NoofmilsN/lOHCl 1. .75 

No. of mils 26 0. .25 

Time of digestion in minutes . . No 

digestion 98 42 28 19 



3 


4 


5 


.50 


.75 


1.00 


.50 


.25 


0.00 



3 


4 


5 


.50 


.25 


0.00 


.50 


.75 


1.00 



3 


4 


5 


.50 


.25 


0.00 


.50 


.75 


1.00 



900 ORGANIC SUBSTANCES 

If the solutions to be tested are not clear they should be filtered 
repeatedly through a hardened filter. If, however, it be found that they 
cannot thus be clarified, check tubes for comparing the end digestion 
products should be made containing the varying amounts of the prepa- 
ration made up with N/10 HC1 in place of ricin. 

After the addition of the solutions to be tested, the test-tubes are 
immersed in the 37.5° C. bath at once, preferably placed in corresponding 
order in a partitioned square or oblong wire rack, such as is used in bacterio- 
logical work. The tubes are shaken and examined from time to time 
for one or two hours, or overnight in the case of very weak solutions. 
The time of beginning the digestion and also the time in minutes of com- 
plete digestion for each tube should be noted (preferably with a stop 
watch) as indicated in the tables above given. 

If the rate of digestion is the same in each series 3 contains exactly 
.1 per cent of pepsin, the amont present in the original solution being .2 
per cent. If the rate is more rapid in I than in II or III it is stronger, 
the comparative strength being closely indicated by the time of action 
in the tubes containing less of the solution. If the rate of clearing is 
most rapid in III, the solution contains some substance which interferes 
with the action of the pepsin, and this must be removed in some way as 
by dialysis * or evaporation in vacuo or at a low temperature until, upon 
reexamination, and further dilution or concentration, the rate of diges- 
tion is identical or nearly so in each series. One mil of 26 represents 
.001 gram of pepsin. 

Smaller quantities of pepsin may be determined in the same way by 
comparing with more diluted solutions of standard pepsin. As small a 
quantity as .00005 gram of U. S. P. pepsin can thus be readily detected 
by its nearly complete solvent action on the ricin ppt. inside of two hours 
and .000005 gram shows marked action on the ricin inside of the same 
time. After four hours 7 digestion, the absence of any appreciable solvent 
action, as judged by ocular inspection, indicates the absence of pepsin. 
The results should be expressed in per cent calculated on the basis of 
pepsin of U. S. P. quality, being 100 per cent. 

The proteolytic value of pills, tablets, powders, and liquid prepara- 
tions containing pepsin may be determined by following the general 
directions recommended in these methods. In all cases due regard must 
be taken of the reaction of the solution before it is added to the egg albu- 

1 Dialysis tubes are made by pouring collodion into test-tubes or small Erlenmeyer 
flasks allowing it to dry a little, adding more collodion and drying again two to five 
minutes or until the collodion does not adhere to the finger when touched, and then 
removing the film and the glass and plunging it at once into water. The films should 
be kept moist until used. The special advantage of these tubes is that they are emi- 
nently adapted for quantitative work. 



PROTEINS AND DIGESTIVES 901 

men. If alkaline it should be neutralized and rendered slightly acid with 
dilute hydrochloric acid. The presence of preservatives and inhibitory 
substances must be determined. 

Papain 

Commercial papain consists of the inspissated juice of the Carica 
papaya or paw paw, usually mixed with starch and sometimes the juices 
of other vegetable growth, some of which have been found to be extremely 
toxic. Commercial papain is sometimes adulterated with pepsin and 
while pepsin is probably more valuable as a digesting agent, its admixture 
with paw paw juice and sale at an exorbitant figure for papain is not to 
be commended. 

The ferment of papain acts best in a slightly alkaline media. It may 
be concentrated from the dried juice by dissolving it in water, dialyzing, 
and precipitating with alcohol. Papain either in the crude or concen- 
trated form is used in the preparation of a limited number of digestive 
products. In the tropics the juice is used by the natives in the treatment 
of eczema, warts, intestinal worms, ulcers, and many lands of foul sores, 
and in diphtheria to dissolve the false membrane in the throat. Its 
greatest use, however, is for the purpose of rendering tough meat tender. 
In this respect paw paw juice possesses the property of pineapple juice, 
the latter being largely employed in the preparation of beef peptone. 

In testing papain and the preparations containing it the following 
method of Rippetoe : is recommended : 

Prepare egg albumen as directed under pepsin assay U. S. P. 9th 
revision. Introduce into a 4-oz. wide-mouth flint bottle 40 mils of a .1 
per cent sodium hydroxide solution and add 10 grains of the disintegrated 
albumen; stopper the bottle and shake vigorously until the albumen 
is broken up. Then add the papain in fine powder and mix by shaking 
gently for fifteen seconds. Place the bottle in a water-bath for six hours, 
removing the bottle every ten minutes and shaking gently for fifteen 
seconds. At the end of this period transfer the mixture to a 100-mil 
graduated stoppered cy finder, rinse the bottle with water, add the rinsing 
to the mixture and make the volume up to 70 mils with water. Set the 
cylinder aside and after standing for one hour read off the volume of the 
deposit. The deposit may be read a second time after standing sixteen 
to eighteen hours (overnight), which seems to give more positive results, 
especially if the volume is large. 

The method is also applicable for determining the digestive value of 
pineapple juice. A sample of dry pineapple juice, using 1 gram of dry 
juice, neutralized with sodium hydroxide, added to 10 grams of the 
1 Journal of Industrial and Engineering Chemistry, 4, 1912, 517. 



902 ORGANIC SUBSTANCES 

albumen in 35 mils .1 per cent sodium hydroxide solution, with three 
hours' digestion, left a residue of 2 mils, reading after eighteen hours, 
while a blank read 41 mils. 

Shelly * suggests the following modification of Sorensen's test for assay- 
ing papain. Four grams casein (Hammerstein) are dissolved in 100 mils 
of alkali solution containing 4 mils N/l sodium hydroxide. To 25 mils 
of this solution are added 25 mils water containing .1 gram dried juice 
and the mixture digested in an incubator at 37° C. for four hours. To 
20 mils of the liquid are added 10 mils of a 40 per cent formaldehyde 
solution just neutralized with N/5 sodium hydroxide. This mixture, 
equivalent to .04 gram of sample is titrated with N/5 sodium hydroxide, 
using phenolphthalein, and at least 1 mil should be required to neutralize 
the amino acids formed, after subtracting the amount required by a similar 
mixture without the juice. 

Thorburn's Method. 2 — .4 gram of papain and .75 gram sodium bicar- 
bonate are dissolved in 100 mils of distilled water and heated to 50-55° C. 
Lean round steak is scraped to a pulp, rejecting gristle, fat, etc.; 
10 grams are placed in a 200-mil digestion flask, the papain-sodium bicar- 
bonate solution added and digested for four hours, maintaining a temper- 
ature of 50-55°. The flask is shaken every ten minutes and at the end 
of the digestion the contents of the flask are poured into a measuring 
cylinder and allowed to stand at rest for one-half hour. Not more than 
10 mils of residue should remain. A blank digestion of the meat pulp 
and bicarbonate should be run simultaneously with the papain digestion. 
After reading the volume of the residue, the mixture is warmed to 50-55° 
1.5 mils concentrated hydrochloric acid is added and again digested for 
four hours, shaking at ten-minute intervals. At the end of this period 
the volume of the residue should be less than 3 mils. 



Pancreatin 

Much has been written concerning the ferments of the pancreas and 
the activity of commercial pancreatin preparations. The characteristic 
ferments of the pancreas include amylopsin, a starch digestant, trypsin, 
a protein digestant, and steapsin, a fat-splitting lipase. 

Pancreatin is extracted from the pancreas of the hog by water or very 
dilute acid, the solution precipitated by means of alcohol, and the pre- 
cipitate dried at 40° C. 

Pancreatin is used as a medicinal agent in a form representing a com- 
mercially high concentration of the active ferments, such as pancreatin 
pure and saccharated pancreatin. It is made up with pills and tablets 

1 Analyst. 39. 170. 

2 J. Amer. Pharm. Assn., 1915, 4, 224. 



PROTEINS AND DIGESTIVES 903 

alone and with other ferments, with inspissated oxgall, Nux Vomica, 
Taraxacum, colocynth, bismuth salts, aromatics, salol, etc. Enteric pills 
of pancreatin are coated with keratin or salol, these agents being sup- 
posedly undissolved in the stomach, but allow the pills to pass into the 
intestine, where it is disintegrated by the alkaline medium, and the digest- 
ive made available. Pancreatin is an important remedy in intestinal 
indigestion. 

Liquid pancreatin preparations are usually in the form of elixirs, and 
may contain pepsin, bismuth and ammonium citrate, strychnin, rhubarb, 
Hydrastis, and other tonics and stomachics. Pancreatin is also com- 
bined with malt extract. 

The amylolytic value of pancreatin and its preparations is determined 
as follows : 

Method for the Routine Valuation of Diastase Preparations, by W. 
A. Johnson. 1 — A standard starch paste is prepared from potato starch 
which has been purified by washing with water, and dried firstly for three 
hours in a current of air, and subsequently for four hours at 80° C, so as 
to contain 90 per cent of anhydrous starch; 22.22 grams of this starch 
( = 20 grams of anhydrous starch) are mixed with 100 mils of cold water, 
and the mixture poured into 800 mils of boiling water, boiled for ten 
minutes, and made up to 1000 grams. In each test 50 grams of the paste 
are used in 250-mil flasks clamped in a water-bath kept at 40° C, and 
ten minutes is fixed as the time of action. In the case of liquid malt 
extracts, about 10 mils diluted to 100 mils are used, while 200 to 500 mg. 
of dry preparations in 100 mils of water are usually suitable quantities. 
Definite quantities of these dilute liquids (say 1 mil to 6 mils) are added 
to the flasks containing the starch paste, and after about eight minutes, 
a few drops are tested with iodin solution (2 grams of iodin and 4 grams 
of potassium iodide in 250 mils). The test is repeated with 100 mils of 
starch paste in the different flasks, just as in Lintner's method of determin- 
ing diastatic activity, new limits being found between which the real 
value must lie, and in every case the disappearance of all color is taken 
as the end-point. In expressing the results in starch-converting power, 
allowance should be made for the fact that the statements of the manu- 
facturers appear to be based upon results obtained with commercial starch 
which contains about 15 per cent of water. 

The tryptic energy of pancreatin is determined as follows by the method 
of Field and Gross : 

A casein solution of .2 per cent strength is prepared by dissolving 
100 mg. of pure casein in 2 mils of N/20 sodium hydroxide, by aid of 
very gentle heat, and diluting to 50 mils. A dilute acid is prepared with 
50 mils of alcohol, 49 mils of water and 1 mil of 100 per cent acetic acid. 
1 Jour. Am. Chem. Soc, 1908, 30, 798. 



904 ORGANIC SUBSTANCES 

The trypsin solution is made by dissolving in the proportion of 20 
mg. to 50 mils of water. 

Six portions of the casein solution of 5 mils, each containing 10 mg, 
of casein, are measured out, and diminishing portions of the ferment solu- 
tion are transferred to test-tubes, but always made up to 5 mils. For 
the milligram of casein the weights of ferment may be taken as follows: 
2 mg., 1.3 mg., .8 mg., .5 mg., .3 mg., and .1 mg. The series of test-tubes 
containing casein and ferment so charged are incubated one hour at 40° C. 
and then withdrawn from the bath. To each tube 3 drops of the dilute 
acetic acid are added. If full digestion has taken place the acid fails to 
produce a precipitate. The last tube in which no precipitate is formed 
gives an approximate measure of the digesting power of the ferment, 
which may be sufficient. 

A closer result may be obtained by making up a new series of ferment 
solutions of just one-tenth the strength of the last. These are to be 
incubated with the casein solution in the same way, the final tests being 
made as before. 

When tested in this manner, 1 part of trypsin should digest at least 
75 parts of casein. 

Method for Determining the Tryptic Value of Pancreatin, C. F. 
Ramsay. 1 — The materials required for the test are as follows: .5 gram 
pancreatin added to sufficient distilled water to make 50 mils of solution; 
900 mils of milk containing 1.8 grams of sodium bicarbonate; 2 grams 
of rennin (1 : 30,000 in ten minutes or equivalent) and 1 mil of 6 per cent 
acetic acid (U. S. P.) added to 50 mils of distilled water. 

After warming the milk, place exactly 50 mils in a cylindrical tube 
of about 100-mils capacity. Prepare several such tubes and place in a 
water-bath, maintaining the temperature at 40° C. Add to the tubes 
of milk the following amounts of pancreatin solution : 

Mils 

8.33 (1 : 600) 

7.69 (1 : 650) 

7.14 (1 : 700) 

6.66 (1 : 750) 

6.25 (1 : 800) 

In each case note the exact time when the pancreatin is added, mix 
well, and after digesting fifteen minutes place 5 mils of the digested milk 
in a test-tube, add 3 mils of the rennin solution, and shake well. No 
precipitate indicates that the casein has all been peptonized and that the 
pancreatin is stronger than the strength tested. For example, if there 
was no precipitation at 1 : 700, but there was a precipitation at 1 : 750, 
1 Jour. Ind. and Eng. Chem., 3, 1911, 823. 



PROTEINS AND DIGESTIVES 905 

then it would be necessary to run more digestions between 1 : 700 and 
1 : 750. Make a fresh solution of pancreatin and use the following 
amounts : 

Mils 

7.04 (1 : 710) 

6.94 (1 : 720) 

6.84 (1 : 730) 

6.75 (1 : 740) 

In this manner it can be determined quite accurately how many times 
its own weight of milk a given sample of pancreatin will peptonize. In 
order to get accurate results the test must be carried out strictly in accord- 
ance with directions. As stated above, acid will precipitate peptonized 
milk, therefore just enough acid is added to the rennin solution so that 
3 mils of this solution will neutralize the sodium bicarbonate in 5 mils of 
the peptonized milk. Then the rennin will do its work, for it will not 
form the precipitate in an alkaline solution. 

Attention must be called to the fact that pancreatin in a neutral 
solution deteriorates quite rapidly. Therefore this solution should be 
made up the last thing, so it can be added immediately to the milk. The 
amount of pancreatin solution suggested is sufficient for testing the 
strengths as indicated. 

Determination of Milk-Curdling Properties. — .16 gram pancreatin 
and .65 gram sodium bicarbonate are placed in a 500-mil flask or bottle, 
50 mils water at a temperature of 45° C. are added, the whole well shaken 
and allowed to macerate fifteen minutes. While this is going on 250 mils 
of fresh milk are warmed to 45° C. and, at the end of the maceration 
period, added to the pancreatin solution, mixed and maintained at 45° 
for one and one-half hours. The container is gently agitated from time 
to time during the first half hour to disintegrate the curd and at the end 
of this time there should be no appreciable curd. At the expiration of 
one and one-half hours there should be no appreciable curdy mass. 

No quantitative methods have been reported for determining the 
lipase action. Mellanby and Wooley have determined that steapsin is 
very unstable. In alkaline solution at 40° it decreases 10 per cent an hour, 
50°, 50 per cent an hour and at 60° is completely destroyed in five minutes. 
In the acid solution its destruction depends on the H ion concentrate. 
It is stable in the presence of large quantities of the higher fatty acids, 
but is destroyed quickly by small amounts (.02 NHC1) of free mineral 
acids. It is rapidly destroyed by trypsin. Serum or egg albumin pro- 
tects steapsin from trypsin in activating pancreatic juice because of the 
presence of anti-trypsin in them. The action of steapsin is accelerated 
by bile and bile salts, but unaffected by electrolytes such as neutral salts. 



906 ORGANIC SUBSTANCES 

Bauer, 1 in reporting some experiments performed with pancreatin 
on free fat, describes a process which might be useful in a study of the 
lipase action. 

In using these preparations they are first formed into a homogeneous 
paste with water, which is then mixed with the fat to be hydrolyzed in 
the proportion of about 5 per cent. When the oil or melted fat is mechani- 
cally stirred with the paste, emulsification soon occurs. After thirty 
minutes to one hour, 5 per cent sodium carbonate solution is gradually 
added, the addition being so regulated that the emulsion when tested with 
red and blue litmus paper always produces a violet stain on each. After 
about one to two hours the requisite amount of alkali (corresponding to 
about 25 per cent of the fatty acids) will have been added, and the mass 
will usually have become too thick from the separation of fatty acids for 
the stirring to be continued. The mass is then left to itself. After five 
hours from 60 to 80 per cent of the fat will usually have been hydrolyzed, 
and the hydrolysis will be complete in one to four days. In one of the 
typical experiments quoted, 100 grams of ox-tallow were melted and mixed 
at 40° C. with 6 grams of pancreas powder made into a paste with 60 mils 
of water. The mass was stirred for an hour at 35° C, after which 80 
mils of N/l sodium carbonate solution were added little by little. After 
five hours 66 per cent of the fat had been hydrolyzed, and the reaction 
was complete in four days. 

If hydrolysis ceases after a time when pancreas-lipase is allowed to 
act on a fat (almond oil), this is due to an alteration of the activity of the 
enzyme; further hydrolysis takes place if a fresh quantity of pancreatic 
juice be added, and sometimes, also, on addition of a fresh quantity of 
the fat. The hydrolysis of fat by fresh active pancreatic juice is acceler- 
ated, but not increased, by addition of bile. The hydrolysis is com- 
pleted more rapidly if the pancreatic juice be added in successive portions; 
in this case, addition of bile does not accelerate the hydrolysis, but indeed 
sometimes retards it. 

There are a number of commercial preparations of the pancreas gland 
which contain larger quantities of the ferments, or at least show greater 
digesting power, than the standard pancreatin of the Pharmacopoeia. 
Some of these have received distinctive names such as Holadin, Panase. 
Some firms claim to have succeeded in concentrating a trypsin compara- 
tively free from other digesting agents, which has a proteolytic value con- 
siderably greater than pancreatin. These products are usually desig- 
nated as Trypsin with the name of the manufacturer hyphenated. 

Much criticism has been directed toward those manufacturers who 
offer digestive preparations containing simultaneously pepsin and pan- 
creatin, but the results of recent experiments seem to indicate that these 
1 Soc. Chem. Ind., 29, 1909, 149. 



PROTEINS AND DIGESTIVES 907 

ferments exercise no destructive action upon one another, and that with 
the proper degree of acidity they can be kept in the same solution perma- 
nently for two and one-half years at least, the loss of activity noted by 
other observers having been due entirely to the reaction of the solution 
and to the degree of such reaction. Solutions containing 10 per cent 
each pepsin and pancreatin, containing HO in graduated strength, from 
.075 to .65 per cent volume absolute, after two and one-half years, have 
retained their full pepsin activity. Those containing less than .35 per 
cent have retained their full trypsin activity, and those of .075 per cent 
have retained in full the amylopsin activity with that of the trypsin and 
pepsin. 

Pepsin and pancreatin can be administered in such a solution, or 
mixed together in dry form, in all proportions, and the pepsin will retain 
its full proteolytic power and the pancreatin both its full amylolytic and 
tryptic activity, which latter is developed after passing the stomach and 
becoming mixed with the alkaline secretions of the intestine. 1 

AMYLOCLASTS 

The chief starch-converting products of medicinal importance are 
diastase, malt extract, and pancreatin. The latter has already been 
considered. The commercial diastases are more or less concentrated 
forms of the enzyme, which are prepared either by growing the fungus 
on wheat bran and extracting with water, or by extracting malt, con- 
centrating the aqueous solution under reduced pressure, and precipitating 
with alcohol. The crude diastase is then dried, or if a liquid preparation 
is desired, it is made up with the filtered precipitate. 

Diastase is used alone for the treatment of ailments arising from 
faulty digestion of starch, and is dispensed in tablets, capsules and in 
liquid form. It is also combined with other digestants in general remedies 
for dyspepsia. 

The activity of diastase products is determined by measuring the 
amount of maltose produced in an excess of soluble starch, or by the 
power of the enzyme to form products which no longer give a color with 
iodin solution. Both of the methods can be used with diastase, but the 
former is unsatisfactory for malt extracts because of the relatively small 
amount of active enzymes present admixed in the first place with a con- 
siderable quantity of maltose. The second method is the simplest and 
most rapid, and is the one generally employed in commercial work. The 
success of the operation depends on the close adherence to details, and 
these are well emphasized in the method of Francis which was originally 
worked out for testing Taka-Diastase. 

1 A. Zimmerman, Jour. Ind. and Eng. Chem., 3, 1911, 751. 



908 ORGANIC SUBSTANCES 

Taka-Diastase Test, 1-150 in Ten Minutes. Solution for Diastase. — 
Weigh out very accurately .1 gram diastase. Transfer to a small mortar 
containing a small quantity of water and grind the mixture. Transfer 
to a 75-mil measuring flask, washing out the mortar very carefully, the 
washing being poured into the flask and adjusted to 75 mils. 

Ten mils of the above solution (containing .133+ gram of diastase) 
will convert 150 times its weight (2 grams) of starch into hydrolyzed 
derivatives in ten minutes. 

Standard lodin Solution. — Dissolve 2 grams of pure iodin in q. s. H2O 
containing 4 grams KI and adjust to exactly 250 mils. 

For the test dilute 1.5 mils of the solution to 1000 mils with distilled 
water. Fill this dilution into 2-ounce clear vials, putting 50 mils (meas- 
ured by means of a measuring flask) into each. Place vials on a white 
porcelain slab. (The strong solution of iodin should be kept in a green 
or amber bottle in a dark place.) 

Starch Paste. — Pour about 900 mils of distilled water into a tared 
vessel (preferably copper) and bring to vigorous boiling. Into this 
pour slowly 20 grams starch suspended in about 30 mils of cold distilled 
water, stirring vigorously. Stir well and continue to boil for ten minutes 
so as to produce a homogeneous thin jelly (use only absolutely neutral 
potato starch). Place container and starch paste on balance (with 
tare) and add distilled water q. s. to adjust weight of starch solution 
to exactly 1000 grams. Cool with vigorous stirring to 40° C. If paste 
is not absolutely uniform discard it, as lumps invalidate the test. 

Provide a sufficient number of cylindrical glass tubes, into which, 
after counterbalancing, pour exactly 100 grams starch paste. Nearly 
immerse the tubes of paste fitted with rubber stoppers in a water-bath 
at 40° C. and allow to stand until contents have attained this temperature; 
after which the digestive solution is added and test begun. 

Water-bath. — In order to have an even temperature it is best to 
arrange a metal water-bath containing a perforated rack. Put in the 
proper measure of water and keep at a temperature of 40° C. by means 
of a gas burner. Large flat-bottomed tubes are best suited for containing 
the starch solution, but vials of any kind having wide mouths can be used. 

Digestion. — Add 10 mils of the diastase solution accurately measured 
with pipette to starch solution in the tube, close the tube by means of a 
tightly fitting rubber stopper and shake vigorously, meantime note the 
minute and second at which shaking began. Place in water-bath and 
allow digestion to proceed, shaking the tube occasionally to prevent the 
formation of a ring of starch around the upper surface of the liquid, which 
does not digest so rapidly and interferes with the end reaction. 

At the end of ten minutes' digestion fill a medicine dropper with the 
digested solution and drop two drops into one of the iodin vials. Agitate 



PROTEINS AND DIGESTIVES 909 

the contents of the vial; no blue color indicative of starch should be pro- 
duced. 

Method of Sherman, Kendall, and Clark. — The starch paste is pre- 
pared as follows : Enough clean air dry potato starch to contain 10 grams 
of water-free substance is suspended in about 100 mils of cold distilled 
water; enough more distilled water to make one liter is poured into 
a 2- to 3-liter flask immersed in a brine bath and connected with a reflux 
condenser. The bath is then heated and if the water boils the heating 
is stopped so that the water may cool somewhat, then the suspension of 
starch is poured very carefully into the hot water, the heating resumed and 
the paste boiled two hours under the reflux condenser. This long boiling 
renders the starch paste less viscous, more homogeneous and transparent, 
and more easy of digestion by the amylase. 

In order to determine how long the boiling of the starch paste should 
be continued, experiments were made in which 250-mil portions of the 
paste were treated with 40 mg. of taka-diastase No. 2 dissolved in 20 mils 
of water and the time required for digestion to products giving no color 
with iodin was determined as follows: Boiled one-half hour, required 
fifty minutes; one hour, required forty-six minutes; one and one-half 
hours, thirty-six minutes; three hours, thirty-three minutes; six hours, 
thirty minutes. Hence boiling beyond one and one-half hours had little 
effect upon the digestibility of the stach as thus determined. Moreover, 
it was noted that up to two to three hours the solutions remained color- 
less while on three to six hours' boiling they became slightly yellowish. 
Two horn's was therefore decided upon as the best length of time for 
boiling the starch paste. 

The paste at a temperature not above 40° is weighed out in 250-gram 
portions (equivalent to 2.5 grams anhydrous starch) into Erlenmeyer 
flasks of 350-400 mils' capacity and immersed in a water-bath kept at 40°. 
The desired amount of enzyme is then introduced along with 20 mils of 
water (in which the enzyme may be dissolved, or which may be used to 
wash it into the flask), the contents of the flask well mixed and the tempera- 
ature of 40° carefully maintained. The digestion is considered completed 
when .25 mil of the contents of the flask removed and mixed with 5 mils 
of the dilute iodin test solution x in a test-tube shows, when viewed against 
a white background, no color which can be distinguished from that of 
the untreated iodin test solution. The experiment is repeated with dif- 
ferent amounts of enzyme, if necessary, until that amount is found which 
completes the digestion in thirty minutes (d=one minute). The result 
may then be conveniently expressed by dividing the weight of starch 

1 Two grams of iodin and 4 grams of potassium iodide are dissolved in 250 mils 
water. For use, 2 mils of this solution are diluted to 1 liter and 5 mils of this dilute 
solution are employed for each test. 



910 ORGANIC SUBSTANCES 

(2.5 grams) by the weight of enzyme required to digest it under these 
fixed conditions. 

U. S. P. Method for Assaying Diastase. — Mix a quantity of potato 
starch, purified as directed under Pancreatin, equivalent to 5 grams of 
dry starch, in a beaker with 10 mils of cold distilled water. Add 140 mils 
of boiling distilled water, and heat the mixture on a water-bath with con- 
stant stirring for two minutes, or until a translucent, uniform paste is 
obtained. Cool the paste to 40° C. in a water-bath previously adjusted 
to this temperature. Prepare a fresh solution of .1 gram of Diastase in 
10 mils of distilled water at 40° C. and add it to the paste. Mix them 
well and maintain the same temperature for exactly thirty minutes, 
stirring frequently; a thin, nearly clear liquid is produced. Add at once 
.1 mil of this liquid to a previously made mixture of .2 mil of N/10 iodin 
V. S. and 60 mils of distilled water; no blue or reddish color is produced. 

W. L. Baker's Method for Assaying Diastase. — A clean grade of potato 
starch is thoroughly washed and carefully dried at a low temperature 
and finally at a higher temperature to about a 10 per cent moisture con- 
tent. The exact moisture content to be determined in a separate 
experiment. For the test enough of the starch is taken (about 11 grams) 
to make to 500 mils of an exactly 2 per cent (anhydrous) starch content. 
The boiling of the paste should be continued for ten minutes with con- 
stant stirring to keep from burning. For each test quantities of exactly 
25 grams of the paste are weighed in a series of 250-mil flasks placed in 
a water-bath and kept at a temperature of 40° C. The iodin test solu- 
tion is made by dissolving 2 grams of iodin and 4 grams of potassium 
iodide in 250 mils of distilled water, 2 mils of this solution is then diluted 
with pure water to make 1000 mils. The diastase solution is made by 
dissolving or suspending .2 gram of diastase in 100 mils of distilled water. 
The solutions are used in the following way : Definite volume's of the solu- 
tion are added to the different flasks containing the starch solution and 
the mixtures are well shaken. The volumes added may be as follows: 
4 mils, 4.5 mils, 5 mils, 5.5 mils, 6 mils. In eight minutes tests are begun 
by removing volumes of 5 drops from each of the digesting mixtures by 
a pipette, and adding this to 5 mils of the dilute iodin solution in a clear 
white tube standing over white paper. If at the end of ten minutes drops 
from one of the flasks fail to give the iodin reaction, we are ready for the 
more accurate test; for example, the flasks containing 5 mils diastase 
solution did not respond to the iodin reaction, but the one containing 4.5 
mils did, then a second test should be carried out under exact ly the same 
conditions as the former, using 4.6, 4.7, 4.8, 4.9, and 5 mils diastase solu- 
tion to 25 grams of the starch paste. The diastase solution must be of 
the same temperature as the starch paste. The test is carried to the loss 
of all color. The diastase solution should have been just previously made 



PROTEINS AND DIGESTIVES 911 

and, if working for any length of time, fresh solutions should be made from 
time to time, as aqueous solutions of diastase are very unstable and soon 
lose their power of conversion. The dilute iodin solution should not be 
put in the tubes until just before it is needed. 

The method of Johnson used for determining the amylolytic value 
of pancreatin is applicable to diastase and malt preparations. 

Malt Extract 

Malt extract is prepared by extracting ground malt with water and 
concentrating to the consistency of molasses. It is a viscid liquid contain- 
ing from 45 to 55 per cent of maltose, protein, water, ash, and diastase. 
When ready for market it is often treated with 8 to 15 per cent of alcohol. 
Malt extract is often combined with other remedial agents, cod liver oil, 
Cascara sagrada, digestives, hypophosphites, creosote, ferric pyrophos- 
phate, quinin, strychnin, Yerba santa, etc. 

Malt preparations are assayed for digestive power in the same way 
as diastase. 

As remedial agents malt preparations are used almost exclusively for 
their amylolytic value. Malt, however, appears to contain ferments 
possessing proteolytic activity, and attention must be directed to the 
work on this subject which has been conducted by Wahl x and the 
procedure adopted by him in measuring this activity. 

A mixture of preferably about one part of crushed malt and four parts 
of water, inoculated with lactic acid ferment, was subjected to a tempera- 
ture varying between 50 and 60° C. maintained for about thirty minutes to 
destroy all organisms except the one to be propagated for producing the 
desired acid, and holding the temperature of the mash at 50° to 55° C. 
for about twenty-four to fourty-eight hours, during which time from 1 to 2 
per cent of lactic acid is formed. The grains are then separated from the 
liquid, and same is used for the malt extractions made as follows: 

One part, either of finely ground malt (Seek mill set at 1.0) or of coarsely 
ground or crushed malt (Seek mill set at .5), is extracted with four parts 
of the bacterial liquor above mentioned, previously diluted with water 
so as to give the desired strength of 105 per cent acidity. Varying tem- 
peratures were used for the extractions as specified below. 

The peptic strength of the malt extracts was determined by auto- 
digestion and by means of a modified " gelatin liquefying strength" 
method of Schidrowitch. In every instance the peptic strength of the 
malt extract was compared with that of a standard solution of pepsin of 
known strength. The method of conducting the test, as well as the prep- 
aration of the pepsin standard, are given below. 

1 8th International Congress of Applied Chemistry, XIV, 221. 



912 ORGANIC SUBSTANCES 

Preparation of the Gelatin. — Thirty-two grams of the gelatin are 
dissolved in 318 mils of distilled water by gently heating the same. One- 
third of a gram of finely ground egg albumen dissolved in 50 mils of dis- 
tilled water is then added and the gelatin solution cooled to 52° C. The 
temperature is then raised to 85 ° C. in five minutes, and then to 100° C. 
where it is held for ten minutes. While still hot the gelatin is filtered into 
a glass beaker containing .5 gram of thymol, which readily dissolves in 
the liquefied gelatin. The solution is then tubed, each tube receiving 6 
mils and the tubes closed with cork stoppers to prevent evaporation. 

Method of Work. — (Testing of proteolytic strength.) The gelatin 
tube is gently warmed, preferably in a thermostat or water-bath, until 
the contents are liquefied. Five mils of the liquid under examination 
are then added to the tube. A blank is prepared at the same time, con- 
taining 5 mils distilled water. The tubes are then placed in an incubator 
held at 37.5° C. and incubated for four hours. After this they are placed 
in ice water at 2° C. and the time required for solidification of gelatin is 
noted. From the number of minutes required by the tube containing 
the liquid under examination, the time required for the solidification of 
the blank is subtracted, and the results tabulated for purposes of com- 
parison. It must be remembered that a malt extract in which the enzyme 
has been destroyed, and which contains from 1 per cent to 2 per cent of 
lactic acid, has a slight power to liquefy gelatin, to the extent of requir- 
ing from one to two minutes longer to solidify than the blank. 

Pepsin Standard. — .15 gram of pepsin of 10,000 strength is mixed 
with 10 grams of powdered sugar, and dissolved in 100 grams of distilled 
water. Five mils of this solution are added to a gelatin tube. The con- 
tents of a tube so prepared requires seven minutes for solidification. 

The amount of coagulable albumen remaining in the malt extracts 
after the same had been subjected to the action of the peptonizing enzyme 
for a given period and at a given temperature was determined by means 
of the coagulation test conducted in the following manner: 

The extract was filtered perfectly clear and then heated to 75° C, 
where it was held for thirty minutes and then allowed to cool to 25° C. 
Ten mils of this solution were introduced into a centrifuge tube graduated 
in 1/10 mils. The tube was placed in the centrifuge and run for a period 
of four minutes, at a speed of about 2500 revolutions per minute. The 
amount of coagulable albumen in the tube is then read in terms of 1/10 mil. 



CHAPTER XXIV 
OILS 

The chemist is often confronted with the problem of determining the 
identity of an oil, or knowing its identity to determine its purity; he may 
be required to determine the kind and amount of an oil in a mixture of 
which a certain oil is one of the constituents; he may have to know the 
different kinds of oils and the approximate proportion of each in a mix- 
ture of oils; and finally it may develop that it is essential to determine 
the identity of an oil used in the preparation of soaps or the salts of the 
higher acids used as the basis of plasters and complex ointments. 

The characteristics of the individual fixed and volatile oils and fats 
are described in great detail in works devoted to this subject, and it is 
not the province of this work to go into a detailed account of all of them. 
But there are a few oils which are used extensively as remedial agents 
or as the components of pharmaceutical preparations to which attention 
must be directed. Of the fixed oils, castor, olive, cod-liver, chaulmoogra, 
croton, theobroma, linseed, and mineral oils are used therapeutically, 
and in addition to these cotton-seed, sesame, sweet almond, arachis 
(peanut) enter into the composition of pharmaceutical mixtures, while 
the solid fatty substances, petrolatum, lard, tallow, and palm oil have 
also an extended use. The most important volatile oils encountered by 
the drug chemist include those of bitter-almond, anise, betula, gaultheria, 
cajuput, chenopodium, copaiba, cinnamon, cloves, eucalyptus, penny- 
royal, juniper berry, peppermint, pinus pumilio, santalwood, sassafras, 
savine, tansy, and turpentine. 

The chemical characteristics, as well as the therapeutic value of some 
of these oils, are dependent on certain well-defined chemical individuals, 
of which often the pure oil is entirely composed, and their consideration 
is best effected among the systematic groups of chemical individuals 
to which the individuals belong. 

General Methods for Examination. — Specific Gravity. — To be deter- 
mined with pycnometer or Westphal balance. 

Refractive Index. — To be obtained with a refractometer. 

Acid Value. — Use 20 grams of fat or oil and 50 mils 95 per cent alcohol. 
Titration figure obtained can be used for calculating free fatty acid as 

913 



914 ORGANIC SUBSTANCES 

oleic. One mil N/10 alkali = .0282 gram oleic acid. One mil N/2 alkali 
= .1410 gram oleic acid. 

Saponification Value. — The saponification value of a fat or oil is the 
quantity of potassium hydroxide (expressed in milligrams) consumed in 
saponifying 1 gram of the fat or oil. It is determined as follows: Weigh 
accurately, in a flask of 200 to 250 mils' capacity, 1.5 to 2 grams of the 
filtered fat or oil and add to it 25 mils of alcoholic potassium hydroxide 
accurately measured from a burette or pipette. Insert into the neck of 
the flask, by means of a perforated stopper, a glass tube from 70 to 80 cm. 
in length and from 5 to 8 mm. in diameter and heat the flask on a water- 
bath for half an hour, frequently imparting a rotatory motion to the 
contents. Then add 1 mil of phenolphthalein and titrate the excess of 
potassium hydroxide with half -normal hydrochloric acid. Make a blank 
test at the same time, using exactly the same amount of alcoholic potas- 
sium hydroxide. The difference in the number of mils of half -normal 
hydrochloric acid consumed in the actual test and the blank, multiplied 
by 28.055 and divided by the weight of the fat or oil taken, gives the 
saponification value. 

Iodin Number. — The iodin value or number of a fat or oil indicates 
the proportion of iodin absorbed under specified conditions. It is deter- 
mined as follows: Introduce about .8 gram of a solid fat or about .3 gram 1 
of an oil, accurately weighed, into a glass-stoppered bottle of 250 mils 
capacity, dissolve it in 10 mils of chloroform, add 25 mils of iodo-bromide 
accurately measured from a burette or pipette, stopper the bottle securely, 
and allow the mixture to stand for hah an hour 2 in a cool place protected 
from light. After this time it must still retain a brown color; if the color 
is not brown a new test should be started, using smaller a quantity of the 
fat or oil. Then add in the order named 30 mils of potassium iodide, 
100 mils of distilled water, and N/10 sodium thiosulphate in small, suc- 
cessive portions, shaking thoroughly after each addition, until the color 
of the mixture becomes quite pale. Then add a few drops of starch and 
continue the addition of N/10 sodium thiosulphate until the blue color 
is discharged. While this test is being carried out, make a blank test by 
mixing exactly the same quantities of iodo-bromide and chloroform and 
titrating the free iodin with N/10 sodium thiosulphate as directed above. 
The difference in the number of mils of N/10 sodium thiosulphate con- 
sumed by the blank test and the actual test, multiplied by 1.269 and 
divided by the weight of the fat or oil taken, gives the iodin value. 

Unsaponifiable Matter. — Weigh from 5 to 10 grams of the oil or fat 
into a 300-mil Erlenmeyer flask, add 100 mils of alcoholic potash (40 

1 .15 to .18 gram for linseed oil, .18 to .2 gram for cod liver oil, and .8 to 1.0 gram 
for oil of theobroma. 

2 One hour is required for castor oil and linseed oil. 



OILS 915 

grams per liter) and heat on the water-bath until saponification is complete. 
A small funnel in the neck of the flask will serve as a reflux condenser. 
After saponification, which usually takes from thirty to forty-five minutes, 
the hot soap solution 1 is poured into a 16-oz. Squibb separator and the 
flask rinsed with two 25-mil portions of 95 per cent alcohol, making a 
total of 150 mils of 95° alcohol. The separator is cooled to room temper- 
ature by shaking under the tap and 75 mils of fight petroleum ether boil- 
ing below 80° added. The petroleum ether dissolves in the alcohol, form- 
ing a clear solution. 

About 125 mils of water are next added and the mixture shaken. 
At this point the petroleum ether will separate and rise to the surface 
of the alcohol-water mixture in a clear layer. The soap solution is drawn 
off into a second separator and extracted twice with 50-mil portions of 
petroleum ether. The combined petroleum ether extracts are filtered 
into a tared beaker and evaporated on the water-bath. The residue is 
dried in a vacuum desiccator and weighed. 

SPECIAL TESTS 
Cottonseed Oil 

Halphen Test. — Mix carbon disulphide, containing about 1 per cent 
of sulphur in solution, with an equal volume of amyl alcohol. Mix equal 
volumes of this reagent and the oil under examination, and heat in a bath 
of boiling, saturated brine for one to two hours. In the presence of as 
little as 1 per cent of cottonseed oil, a characteristic red or orange-red 
color is produced. 

Lard and lard oil from animals fed on cottonseed meal will give a faint 
reaction; their fatty acids also give this reaction. 

The depth of color is proportional, to a certain extent, to the amount 
of oil present, and by making comparative tests with cottonseed oil some 
idea as to the amount present can be obtained. Different oils react with 
different intensities, and oils which have been heated from 200-210° C. 
react with greatly diminished intensity. Heating ten minutes at 250° C. 
renders cottonseed oil incapable of giving the reaction. 

Peanut Oil 

Weigh 20 grams of the oil into an Erlenmej^er flask. Saponify with 
alcoholic potash solution, neutralize exactly with dilute acetic acid, using 

1 The alcohol content of the soap solution after dilution with water should be very 
close to 55 per cent by volume. It is necessary to know the volume of the alcoholic 
potash solution as well as the amount of alcohol used in rinsing the flask. A lower 
content of alcohol than 50 per cent will result in emulsions, while a higher percentage 
than 60 will cause the retention of a large part of the petroleum ether in solution. 



916 ORGANIC SUBSTANCES 

phenolphthalein as an indicator, and wash into an 800- to 1000-mil flask 
containing a boiling mixture of 100 mils of water and 120 mils of 20 per 
cent lead acetate solution. Boil for a minute and then cool the precipi- 
tated soap by immersing the flask in water, occasionally giving it a whirl- 
ing motion to cause the soap to stick to the sides of the flask. After the 
flask has cooled, decant the water and excess of lead acetate solution and 
wash the lead soap with cold water and 90 per cent alcohol by volume. 
Add 200 mils of ether, cork and allow to stand for some time until the soap 
is disintegrated; heat on a water-bath, using a reflux condenser, and boil 
for about five minutes. In the case of oils, most of the soap will be dis- 
solved, while in lards, which contain much stearin, part of the soap will 
be left undissolved. Cool the ether solution of soap to 15-17° C. and 
allow to stand until all the insoluble soaps have separated out (about 
twelve hours). 

Filter upon a Buchner funnel and thoroughly wash the insoluble lead 
soaps with ether. Wash the ether-insoluble lead soaps into a separatory 
funnel by means of a jet of ether, alternating at the end of the operation, 
if a little of the soap sticks to the paper, with hydrochloric acid (1 to 3). 
Add sufficient hydrochloric acid (1 to 3) so that the total volume of the 
latter amounts to about 200 mils and enough ether to make the total 
volume of it 150-200 mils and shake vigorously for several minutes. Allow 
the layers to separate, run off the acid layer, and wash the ether once with 
100 mils of dilute hydrochloric acid, and then with several portions of water 
until the water washings are no longer acid to methyl orange. If a few 
undecomposed lumps of lead soap remain (indicated by solid particles 
remaining after the third washing with water), break these up by running 
off almost all the water layer and then add a little concentrated hydro- 
chloric acid, shake, and then continue the washing with water as before. 
Distill the ether from the solution of insoluble fatty acids and dry the latter 
in the flask by adding a little absolute alcohol and evaporating on a steam- 
bath. Dissolve the dry fatty acids by warming with 100 mils of 90 per 
cent alcohol by volume and cool slowly to 15° C, shaking to aid crys- 
tallization. Allow to stand at 15° C. for thirty minutes. In the presence 
of peanut oil, crystals of arachidic acid will separate from the solution. 
Filter, wash the precipitate twice with 10 mils of 90 per cent alcohol by 
volume, and then with 70 per cent alcohol by volume, care being taken 
to maintain the arachidic acid and the wash solutions at a definite tem- 
perature in order to apply the solubility corrections given below. Dis- 
solve the arachidic acid upon the filter with boiling absolute alcohol, 
evaporate to dryness in a weighed dish, dry, and weigh. Add to the 
weight .0025 gram for each 10 mils of 90 per cent alcohol used in the crys- 
tallization and washing, if conducted at 15° C: if conducted at 20° C, 
add .0045 gram for each 10 mils. The melting-point of arachidic acid 



OILS 917 

thus obtained is 71 to 72° C. Twenty times the weight of arachidic acid 
will give the approximate amount of peanut oil present. Arachidic acid 
has a characteristic appearance and may be identified by the microscope. 
As little as 5 to 10 per cent of peanut oil can be detected by this method. 

Sesame Oil 

Baudoin Test. — Dissolve .1 gram of finely powdered suga,r in 10 mils 
of hydrochloric acid (sp. gr. 1.20), add 20 mils of the oil to be tested, 
shake thoroughly for a minute and allow to stand. The aqueous solution 
separates almost at once and, in the presence of even a very small admix- 
ture of sesame oil, is colored crimson. Some olive oils give a slight pink 
coloration with this reagent. Comparative tests with known samples 
containing sesame oil will differentiate them. 

Villavecchia Test. — Add 2 grams of furfural to 100 mils of 95 per cent 
alcohol by volume and mix thoroughly .1 mil of this solution, 10 mils of 
hydrochloric acid (sp. gr. 1.20), and 10 mils of the oil by shaking them 
together in a test-tube. A crimson color is developed as in the Baudoin 
test, where sugar is used. 

Villavecchia explained this reaction on the basis that furfural is formed 
by the action of levulose and hydrochloric acid and therefore substituted 
furfural for sucrose. As furfural gives a violet tint with hydrochloric 
acid it is necessary to use the very dilute solution specified in the method. 

Cholesterol and Phytosterol 

Introduce 200 to 300 grams of the melted fat into a flat-bottomed liter 
flask. Close the neck of the flask with a three-holed stopper and insert 
through these holes : (1) a reflux condenser; (2) a right-angled glass tube, 
one arm of which reaches to a point 6 mm. above the surface of the melted 
fat, the other being closed a short distance from the flask by means of a 
short piece of rubber tubing and a pinch-cock; (3) a glass tube bent so 
that one arm reaches down to the bottom of the flask and the other serves 
as a delivery tube for a 700-mil round-bottomed flask containing 500 mils 
of 95 per cent alcohol by volume. 

Place the flasks containing the melted fat and the alcohol on a steam- 
bath and heat so that the alcohol vapor passes through the melted fat in 
the liter flask and is condensed in the reflux condenser, finally collecting 
in a layer over the melted fat. After all the alcohol has passed in this 
manner into the flask containing the fat, disconnect the flask from which 
the alcohol has been distilled and attach a tube to the short piece of rubber 
tubing attached to the right-angled glass tube (see (2) above) and siphon 
the alcohol layer back into the alcohol distillation flask. Reconnect as 
at first and again distill the alcohol as in the first operation. When all 



918 ORGANIC SUBSTANCES 

the alcohol has been distilled, siphon it again into the distillation flask 
and extract in the same manner for a third time. 

Discard the fat and retain the alcohol, which now contains practically 
all of the cholesterol and phytosterol originally present in the fat. Con- 
centrate the alcoholic solution to about 250 mils and add 20 mils of potas- 
sium hydroxide solution (1 to 1) to the boiling liquid. Boil for ten minutes 
to insure complete saponification of the fat, cool to room temperature and 
pour into a large separatory funnel containing 500 mils of warm ether. 
Shake to insure thorough mixing and add 500 mils of water. Rotate the 
funnel gently to avoid the formation of extremely stubborn emulsions, 
but mix the water thoroughly with the alcohol-ether-soap solution. A 
clear, sharp separation takes place at once. Draw off the soap solution 
the wash the ether layer with 300 mils of water, avoiding shaking. Repeat 
the washing of the ether solution with small quantities of water until all the 
soap is removed. Transfer the ether layer to a flask and distill the ether 
until the volume of liquid remaining in the flask measures about 25 mils. 
Transfer this residue to a tall 50-mil beaker and continue the evaporation 
until all the ether is driven off and the residue is perfectly dry. If desired 
a tared beaker may be used and the weight of the unsaponifiable matter 
determined at this point. 

Add 3 to 5 mils of acetic anhydride to the residue in the beaker, cover 
the beaker with a watch-glass and heat to boiling over a free flame. After 
boiling for a few seconds, remove the beaker from the flame, cool and add 
35 mils of 60 per cent alcohol by volume. Mix the contents of the beaker 
thoroughly, filter off the alcoholic solution, and wash the precipitates with 
60 per cent alcohol. Dissolve the precipitate on the filter with a stream 
of hot 80 per cent alcohol by volume and wash the insoluble portion well 
with 80 per cent alcohol. Acetates of cholesterol and phytosterol are dis- 
solved while the greater portion of the impurities present (including 
paraffin and paraffin oil if present) remain behind on the filter. Cool the 
combined filtrate and washings to a temperature of 10-12° C. and allow- 
to stand at that temperature for two to three hours. During this time 
the acetates of cholesterol and phytosterol crystallize from the solution. 
Collect the crystals upon a filter, wash with cold 80 per cent alcohol and 
then dissolve them in a minimum amount of hot absolute alcohol. Collect 
the alcoholic solution of the acetates in a small glass evaporating dish, 
add 2 or 3 drops of water to the solution and heat if not perfectly clear. 
Allow the alcohol to evaporate spontaneously, the contents of the dish 
being stirred occasionally to mix the deposit of crystals which form upon 
the edges with the main body of the liquid. As soon as a good deposit 
of crystals has formed, collect them upon a hardened filter, wash twice 
with cold 80 per cent alcohol, and dry by suction, drying finally a,t 100° C. 
for thirty minutes, and determine the melting-point. 



OILS 



919 



The melting-point of the first crop of crystals usually gives definite 
information as to the presence or absence of phytosterol, but the con- 
clusion, indicated should be confirmed by recrystallizing the crystals from 
absolute alcohol and again determining the melting-point. If the crystals 
are pure cholesteryl acetate, the melting-point of the second crop should 
agree closely with that of the first. If phytosteryl acetate is present, 
however, a higher melting-point will be noted, as phytosteryl acetate is 
less soluble in alcohol than cholesteryl acetate. The melting-point of 
cholesteryl acetate is 114° C, that of phytosteryl acetate 125-127° C. 



SUMMARY OF CONSTANTS OF MOST IMPORTANT FIXED OILS USED IN 

MEDICINES 



Oil 


Sp. Gr. at 25° 


Sapon. Value 


Iodin Value 


Rotation 


Castor 


.945 -.965 
.910 -.915 
.9196-. 922 
.935 -.950 
.951 

.925 
.973 

.925 -.930 
.915 -.921 
.916 -.921 
.910 -.915 
.911 -.926 
at 15° 


179-185 
190-195 
180-190 
200-215 
213 

197 

188-195 

187-195 

190-198 

188-193 

191-200 

186-194 


83-88 

79- 90 

150-170 

104-110 

103 

152 
33- 38 

170 

105-114 

103-112 
93-100 
83-101 


+23.4°-+26.1° 


Olive 




Cod Liver 




Croton 

Chaulmoogra (true oil) 

Gynocardia Oil (false Chaul- 
moogra) 


Strongly dexto 

(a) jD + 52° 


Theobroma 

Linseed 




Cotton S'^ed 

Sesame 

Sweet Almond 




Peanut 





Cod-liver Oil 

The oil expressed from the fivers of the cod is the most extensively 
used medicinal oil. It is dispensed in the free state and as an emulsion, 
and in the latter form is often combined with sodium and calcium hypo- 
phosphites, creosote, wine, and phosphoric acid. In soluble elastic capsules 
it is combined with phosphorus, creosote, and iodoform. The emulsions 
of the oil are not to be confused with the preparations containing cod- 
liver extract. The latter is really a mixture of proteins, animal acids and 
salts obtained by extracting the livers with an alcoholic menstruum, and 
little or no actual oil is present. This cod-liver extract is combined with 
iron and manganese peptonates, hypophosphites, strychnin, bile acids, 
wine, and flavoring agents. The combinations are sold under various 
trade names, and the labels and literature usually contain some reference 
to the presence of the cod-liver principles. 

The composition of cod-liver oil has been surrounded with more or less 



920 ORGANIC SUBSTANCES 

mystery, and its virtues have been attributed to many causes, such as 
nitrogenous or alkaloidal constituents, the presence of organic iodin or 
of organic phosphorous, the absence of hydroxyl glycerides, etc., and it 
is of interest to present a few facts concerning the actual composition of 
a pure medicinal oil. 

The limits of specific gravity for a high-grade cod-liver oil are about 
.9196 to .922 at 25°; the iodin value averages between 150 and 170, with 
a few oils going above or below these figures; the index of refraction runs 
from 1.4783 to about 1.4822; the saponification value is from 180 to 190; 
and a pure oil does not congeal above — .11° C. In connection with the 
saponification value it should be stated that the determination is of little 
moment except in cases of very fight oils. With dark oils the end-point 
becomes so obscured that accurate titration is impossible. 

In one of the color tests recommended for cod-liver oil, 20 drops of 
the oil are placed in a watch-glass over white paper and treated with one 
to two drops of concentrated sulphuric acid, carefully added to avoid 
mixing, then the acid and oil intimately stirred, and the color change noted. 
When stirred, pure light-colored oils give a play of colors: at first purplish 
red, changing quickly to a ruby red, then a deep mahogany color and more 
slowly to a warm brown; around the edge, the thin layer of liquid assumes 
a pale-blue tinge, and on standing from one-half to one hour a purple 
shade develops, the mixture becoming dark brown on long standing. 
Some oils, especially the darker colored, pass directly to the mahogany 
and dark-brown stage without showing the reds, and become almost black 
on standing, with little or none of the purplish ring around the edge. 
Cusk and pollock liver oils, even after four years' standing, give the same 
play of colors as genuine cod-liver oil. This test may be varied by dis- 
solving the oil in carbon bisulphide or chloroform and adding sulphuric 
acid; but the same general results are obtained, though the shades of color 
are perhaps slightly different. 

The test with fuming nitric acid, described in the Pharmacopoeia, 
gives varying results. Some samples of known purity do not become 
rose red, but turn purple or brownish and then change to brick red. The 
description of this test is incomplete, as the color is first pale rose, which 
soon gives way to a brick red and very gradually changes to yellow. In 
some cases, also, the brick-red color does not change to yellow, but to a 
brown; and in others again it does not fade to a purple yellow at all, but 
remains reddish. 

In connection with the actual composition of cod-liver oil, attention 
must first be called to some work performed in 1890 by Gautier and 
Morgues, and in 1906 by Bull. The investigations of the former were 
concerned with the nitrogenous constituents of cod-fiver oils, and of the 
latter with the actual composition of a pure oil.' 



OILS 921 

Gautier and Morgues found that the dark-colored oils, which, by the 
way, are never used medicinally and are really extracted from livers that 
are partially putrefied, contain the following well-defined nitrogenous bases: 
butylamine, amylamine, hexylamine, delrydrolutidine, aselline, and mor- 
rhurine. With the exception of the two latter, these bases have been 
known for some time, and no special virtue is attributed to them. Bull, 1 
working with pure oils free from nitrogen, endeavored to identify the 
acids which made up the glycerides. He converted the mixed acids into 
their methyl esters, fractionated them, and separated the following acids: 
oleic, myristic, palmitic, erucic, gadolinic, and a new acid. 

The work done by Tolman and myself at the Bureau of Chemistry 
fully verified the conclusions of these workers and showed that a high- 
grade oil contained no nitrogenous constituents nor any iodin or phos- 
phorus compounds, but was a mixture of neutral glycerides, and that its 
good effects are probably attributable to its being a ready assimilable fat. 

The figures given in the 9th revision of the U. S. P. as applying to a 
cod-liver oil of standard purity are nearly all incorrect, and the test for 
the limit of free fatty acids is vague and of no value. Oils of high purity 
will often contain nearly 1 per cent of free acid. The figures and the color 
tests together are not limited to cod-fiver oil, but will apply equally well 
to carefully refined oils from other fish fivers; though it should be stated 
that in this investigation the oils from the livers of American cod and 
other American fish lose their original character and become unfit for 
medicinal use after three to four years. 

The fact that highly refined liver oils show practically the same con- 
stants and answer the same tests is of interest to those who are engaged 
in the oil business, as it shows the possibilities of a new industry for utiliz- 
ing oils of hitherto valueless livers, not for the purpose of adulterating 
cod-fiver oils but for their own value as medicinal agents. 

It will be noted that the determination of the identity of a fish oil is 
not a matter of absolute certainty. The most rational method would 
be the conversion of the glycerides to the metlryl esters of the acids and 
identif3 T ing the components of the mixture, which is a long and tedious 
operation and almost impossible of attainment unless the sample is of 
sufficient bulk. Another complication arises from the fact that the com- 
position of the glycerides of oils other than cod-liver oil has never been 
determined. Hence it appears that about all an analyst is justified in 
saying is that the oil is a fish oil and perhaps a fish liver oil. 

If it is desired to determine the quantity of oil in a capsule, a funnel 
with a wide bowl should be placed so that it can drain into a graduated 
cylinder and 5 to 10 capsules slit with a knife, dropped into the bowl of the 
funnel and the contents allowed to drain into the graduate. 

1 Berichte, 1906, 39, 3570. 



922 ORGANIC SUBSTANCES 

Emulsions are examined for their content of oil by transferring a 
measured quantity to a separatory funnel, adding water if very thick and 
then a quantity of alcohol until the emulsion breaks. This procedure does 
not always suffice, and it may be necessary to warm the diluted emulsion 
by rotating the containing vessel over the steam-bath, or to cool in a freez- 
ing mixture, or to add lead acetate. After the emulsion breaks up the oil 
can be shaken out with petroleum ether or ether using two or three portions 
and the combined solvent mixtures filtered through a dry filter and evapo- 
rated over the steam-bath. The residue is then measured or weighed 
and the figure may be used for obtaining a fairly close approximation of 
the quantity present in the emulsion. With substances of this nature 
it is difficult to obtain results of great accuracy, because the oil gains 
weight when heated and it is difficult to remove the last traces of the 
solvent. 

Castor Oil 

Castor oil, which is expressed from the seeds of Ricinus communis 
(Euphorbiacese) is a popular laxative remedy. It is usually dispensed 
in capsules and is sometimes combined with Podophyllum resin. The 
capsules of Aspidium (Malefern) used for the expulsion of tape worm con- 
tain castor oil. It is combined with croton oil in veterinary remedies. 

Castor oil is the only commonly occurring non-volatile expressed oil 
which is readily soluble in 95 per cent alcohol and in 5 parts 90 per cent 
alcohol, and this simple test is sufficient to indicate the identity of a sample 
under examination. It also deviates the plane of polarized light to the 
right unless it has been heated to 270° C. It is composed chiefly of the 
glyceride of ricinolic acid. 

Castor-oil mixture is an emulsified preparation of the oil with acacia 
flavored with cinnamon and orange flower water. 

Castor oil is incorporated with magnesium oxide and sold as dry powder. 

Olive Oil 

The use of this oil as an internal lubricant and a nutritive agent is on 
the increase. It is prepared in enormous quantities and marketed in a 
state of great purity. Besides being sold by itself as a medicinal agent, 
it is combined with other drugs to furnish a bland medium for adminis- 
tration and the additional therapeutic action. It will be found combined 
with apiol; Cascara sagrada extract; copaiba; pennyroyal oil; creosote; 
oleoresin malefern and kamala, oleoresin saw palmetto; salol, cubeb oleo- 
resin; santal oil and pepsin, etc. 






OILS 923 



Sweet Almond, Peach, and Apricot Kernel Oils 

These three oils resemble each other closely in appearance and proper- 
ties, and may be and probably often are substituted for each other. For 
all practical purposes their properties are identical, and are closely allied to 
olive and other bland fixed oils like cottonseed and sesame. 

Most of these bland oils which are now obtainable in a state of great 
purity are used as vehicles and for their lubricating and emollient value 
in inhalants and embrocations. 

In the early days of the administration of the Food and Drugs Act, 
the importation of these three oils was the subject of considerable scrutiny, 
and their absolute differentitation was found to be a matter of difficulty. 
The practice of mixing one with another was evidently in vogue, and the 
actual determination of the composition of such a product was practically 
impossible. As with other oils, the only feasible way of showing any dif- 
ference between them would be to determine the character of the mixed 
glycerides, and to apply the knowledge gained in examining the suspected 
samples. At present the dependence on the difference in color reactions 
given with certain reagents is too uncertain to be used as a final criterion 
of differentiation. The improvements in the methods of refining oils 
have advanced to such a degree that it is possible to eliminate many of 
the impurities to which the color tests were probably attributable. Again 
the study of oils has developed the possibilities of manipulation, and by 
simple treatments it is often easy to render an oil incapable of yielding 
some of the simple tests which a few years ago were sufficient for its identi- 
fication. 

Expressed oil of almond is the base of phosphorated oil. 



Croton Oil 

Croton oil from the seeds of Croton tiglam is a component of hepatic 
stimulants and purgative mixtures. On account of its drastic action it 
is not dispensed by itself, but is combined in small quantity with other 
laxative and stimulant drugs which are prepared for use in the form of 
pills and tablets. The combinations are generally of the following types 
aloes, gamboge, Podophyllum resin, Capsicum and croton oil; aloin, 
Nux Vomica, Podophyllum resin, gamboge, Veronica virginica, Capsicum, 
Veratrum viride, calomel and croton oil; Aloes, scammony, myrrh, caraway 
oil, mercury mass, and croton oil. It is also present in some of the liquid 
cathartic mixtures combined with Cascara sagrada. It is sometimes 
employed externally in cases where a strong counter-irritant is desired, 
and in veterinary practice has proven a valuable remedy for lump jaw. 



924 ORGANIC SUBSTANCES 

Compte * recommends the following identification test: When the 
pure oil or a mixture with other oils is shaken with twice its volume of 
absolute alcohol, the clear alcholic liquid poured into a highly concentrated 
solution of sodium potassium hydroxide and the mixture warmed thirty 
seconds in a boiling water-bath and allowed to stand, an intense reddish- 
brown or reddish-violet ring forms at the junction of the liquid. 

If during the analysis of a laxative mixture, an oily substance is sepa- 
rated, a few drops rubbed on the under side of the forearm will cause a 
characteristic eruption if it is croton oil. 

Cottonseed Oil 

This oil is obtainable in a high degree of purity, and is being recom- 
mended as a nutritive, for which purpose it is expected to rival olive oil. 
It is used as a vehicle for camphor, menthol, and other medicinal agents, 
and adds to their virtues the additional value of a lubricant in case of 
sprains and stiffness of the joints. 



Sesame Oil 

Sesame oil is employed as a vehicle and a lubricant, and is one of the 
components of some of the oily preparations extensively advertised for 
their value as local applications to the mammary and external genital 
organs and the abdomens of pregnant women. 

A characteristic test for this oil and which is useful in detecting it in 
admixture with other oils is obtained by shaking 1 mil with 1 mil of con- 
centrated hydrochloric acid containing 1 gram of cane sugar, when a rose- 
red color develops in fifteen minutes, changing gradually to violet. With 
other fixed oils no coloration develops for nearly an hour, 



Chaulmoogra Oil 

This oil has powerful alterative properties, and is used as a remedy 
for leprosy. Its source was for a time uncertain, but it is now known that 
the true oil is expressed from the seeds of Taraktogenos kurzii King. 
Several species of Hydnocarpus, as H. venenata, H. wightiana, and H. 
anthelmintica, yield oils of similar chemical composition, the oil from the 
former being known as false chaulmoogra. 

The oil from Gynocardia odorata, which was considered at one time 
the source of chaulmoogra, has an entirely different make-up. It is also 
a liquid, while the true oil is a soft solid below 22°. 
1 I. Pharm. Chim., 1916, 14, 38. 



OILS 925 

Chaulmoogra oil is optically active and consists to a large extent of 
the glyceryl esters of optically active cyclic acids of the general formula, 
C„H2n-402- Power, 1 who isolated these acids, designated that present 
in largest amount chaulmoogric acid, C18H32O2. This acid melts 68° 
with (o)d56°. A small amount of palmitic acid and a phytosterol are 
present. 

Gynocardia oil is optically inactive and contains none of the members 
of the chaulmoogric acid series. It consists of glycerides of linolic acid 
or isomerides of the same series, palmitic, linolenic, and isolinolenic acids, 
and a phytosterol, melting 133°. The seeds of Gynocardia contain a 
cyanogenetic glucoside, gynocardin. 

True chaulmoogra oil has a high acid value 23-24, while the false oil 
is low, 4-5. 



Oil of Theobroma. Cocoa Butter 

This oil solidifies below 30° C. and has a characteristic odor. It is 
extensively employed as a suppository base and functionates to a slight 
extent in the composition of ointments and salves. 



VOLATILE OILS 

General Methods for Examination. — Specific Gravity. — To be deter- 
mined with pycnometer or Westphal balance. 

Optical Rotation. — To be determined with a polarimeter or saccharim- 
eter. Polarimeters permit the angle of rotation to be read off in degrees 
or fractions of a degree of a circle. Saccharimeters set to measure percent- 
age of sucrose, give readings in terms of divisions of the sugar scale. 

One division Laurent sugar scale equals .2167° angular rotation D. 

One division Schmidt & Hansch sugar scale equals .346° angular 
rotation D. 

Specific Rotatory Powder. — The rotatory power of an optically active, 
liquid substance, observed with sodium light, and referred to the ideal 
density 1, and in the tube having the length of 1 decimeter (100 mm.)., 
is designated as its specific rotatory power. This is usually expressed 
by the term (a) D . Since, however, not only the density of an optically 
active liquid, but also its rotation, is influenced by the temperature, the 
specific rotation varies with the latter. In stating the specific rotation 
it is, therefore, necessary to indicate at what temperature the rotation 
and the density of the liquid have been determined. But for the same 

1 Amer. J. Pharm., 87, 1915, 493. 



926 ORGANIC SUBSTANCES 

temperature the specific rotation of a pure, optically active liquid is always 
a constant number. The temperature used in the text of the Pharmaco- 
poeia is 25° C, except when otherwise indicated. For saccharimeters 
the temperature is fixed at 20° C. by international agreement. 

For calculating the specific rotatory power of an optically active liquid 
substance, or solution of an optically active solid, the following formulas 
are of general application : 

I. For liquid subtances (a) D 



II. For solutions of solids (a) D = 



LXd 
10000 X a 



LXpXd 
or 

10000 X a 



(«); 



LXc 



For calculating these formulas the determination of the following 
factors is necessary: 

a = the angle of rotation of the liquid or solid observed with sodium 
light; 

L = the length of the tube in millimeters; 

d = the density of the active liquid or solution; 

p = the amount of active substance in 100 parts by weight of the 
solution; 

c = the number of grams of active substance in 100 mils of solution. 

Solubility in alcohol of various strengths and in other solvents. 

Saponification Value. — This is actually the sum of the acid and ester 
numbers. The former is the amount of KOH in milligrams necessary to 
neutralize the free acid in 1 gram of the oil. The latter is the amount 
used in the saponification of 1 gram. 

The saponification is conducted in a wide-necked flask of potash glass 
of 100-mils capacity. A glass tube about 1 mm. in length and passing 
through a stopper serves as a reflux condenser. About 2 grams of oil 
are weighed accurately to 1 eg. into such a flask and 10 to 20 mils of the 
N/.5 alcoholic potash solution are added. Previous to this the oil should 
be tested for free acid, an alcoholic solution of phenolphthalein being 
used as indicator. The flask provided with the condensing tube is heated 



OILS 



927 



for half an hour on a steam-bath, and after cooling, the contents are diluted 
with about 50 mils of water and the excess of alkali titrated back with 
half normal sulphuric acid. 

Acetylization. — This is a measure of the alcohols of the Formulas 
GoHigO and Ci H 20 O. 

For the quantitative acetylization 10 to 20 mils of the oil, mixed with 
an equal volume of acetic acid anhydride and 1 to 2 grams of dry sodium 
acetate, are boiled uniformly from one to two hours in a small flask provided 
with a condensing tube which is ground into the neck of the flask. After 
cooling, some water is added to the contents of the flask and then heated 
from one-quarter to one-half hour on a water-bath, to decompose the excess 
of acetic acid anhydride. The oil is then separated in a separating funnel, 
and washed with soda solution and water until the reaction is neutral. 
Of the acetylized oil dried with anhydrous sodium sulphate 2 grams are 
saponified according to the method described above. The amount of 
alcohol, based on the original unacetylized oil, corresponding to the saponi- 
fication number, can be found by the formulas below. 

For the calculation the following formulas may be used; 



196Xsapon. No. , 

1. - — ^ = per cent of ester 



56 



For the Alcohol, ^ 2 . 154Xsa P on - No - 
CioHisO 



3. 



56 
a X 15.4 



£-(aX0.042) 



= per cent of alcohol 

= per cent of alcohol in original oil. 



For the Alcohol, 

C10H20O 



, 198Xsapon. No. , 

1. =^ = per cent of ester 

00 

' 156Xsapon. No. • . , , , 

2. - — ^ = per cent of alcohol 



3. 



56 
aX15.6 



= per cent of alcohol in original oil. 



S - (a X 0.042) 
a = mils of normal KOH used. 
S = grams of acetylated oil used for the saponification. 



928 



ORGANIC SUBSTANCES 



SUMMARY OF CONSTANTS OF THE MORE IMPORTANT VOLATILE OILS 



Oil 



Bitter Almond 

Anise 

Star Anise 

Fennel 

Caraway 

Coriander 

Sandalwood 

Eucalyptus 

Orange 

Cajuput 

Clove 

Cassia 

Chenopodium 

Cubeb 

Juniper 

Lavender 

Lemon 

Peppermint 

Spearmint 

Nutmeg 

Pimento 

Pine Needle (Pinus 

pumilio) 

Rosemary 

Sassafras 

Mustard 

Turpentine 

Thyme 

Copaiba 

Pennyroyal (American) 
Pennyroyal (European. 

Savin 

Tansy 



Specific Gravity at 25° C. 



1.038-1.060 

.978- .988 

.980- .990 

.953- .973 

.900- .910 

.863- .875 

.965- .980 
Variable depending on species 

.905-. 925 

.842- .846 

.912- .925 
1.038-1.060 
1.045-1.063 

.955- .980 

.905- 

.854- 

.875- 

.851- 

.896- 

.917- 

.859- 
1.018- 



Optical Rotation in 100-mm. 

tube 



.925 
.879 
.888 
.855 



.934 
.924 
.048 



.853- .869 

.894- .912 

1.065-1.077 

1.013-1.020 

.860- .870 

.984- .930 

See under drug 

.920- .935 

.930-. 960 at 15° C. 

.903- .923 

.925- .940 



Inactive or not over +0° 
+ 10° to -2° 

0° to -12° 
+ 12° to +24° 
+70° to +80° 
+ 8° to +13° 
-15° to -20° 
Variable usually laevo 

+91° to +98° 
-4° 
-1°10' 
+ l°to - 1° 
-4° to -10° 
-20° to -40° 
0°to -15° 
-4° to -10° 
+57° to +64° 
-23° to -35° 
-38° to -55° 
+12° to +30° 
0° to -4° 

-3° to -10° 
-9° to +18° 
+3° to +4° 

Inactive 

Variable 
Slightly laevo 

+ 18° to +22° 
+ 17° to +23° 
+40° to +60° 
+30° to +45° 



10 ] 



Oil of Bitter Almonds 

The discussion of this oil will be found in the section devoted to Cyano- 
genetic Glucosides. 



Oils of Anise and Star Anise 

These oils are obtained from the fruits of plants belonging to entirely 
different families. The anise plant Pimpinella anisum belongs to the 
Umbelliferse, while the species of Illicium which yield the star anise oil 



OILS 929 

belong to the Magnoliaceae. Both oils contain anethol as their most 
important and valuable constituent, there is also a smaller quantity of 
the isomeric methyl chavicol. The two oils can be distinguished from 
each other only by odor and taste. 

Anise oil is a colorless, highly refractive liquid which solidifies to a 
snow-white crystalline mass, melting 15-19° C. The solidification point 
of a sample of oil furnishes very good indication of the quality of the prod- 
uct, and may be determined as follows: 

Transfer a small quantity of the oil to a test-tube and surround 
it with ice water or chipped ice, or a mixture of ice and salt. Insert a 
thermometer and allow it to remain undisturbed until the temperature 
has fallen to about 5° below the normal congealing point of the oil (in 
the case of star anise this is about 15° C. and the fennel about 3°). Then 
induce crystallization by stirring with the thermometer, removing the 
tube from the bath and continuing until solidification takes place. The 
highest temperature reached during the crystallization is regarded as the 
congealing point. 

Anise oil has been reported adulterated with fennel oil, turpentine, 
cedar wood oil, copaiba, and gurjun balsam oil, alcohol, spermaceti, fixed 
oils. The presence of these adulterants is readily detected by a determi- 
nation of the physical properties. Fennel oil and its stearoptene are the 
common adulterants, but they cause a dextro rotation and are easily 
detected. Pure anise oil undergoes oxidation if carelessly stored or 
exposed to the fight, its specific gravity increases and its tendency to solidify 
disappears. 

Star anise oil is a colorless or yellowish, highly refractive liquid, con- 
gealing between +14 and +18° C, and containing from 80-90 per cent 
of anethol with probably some methyl chavicol, and two terpenes, d-pinene 
and £-phellandrene, making up the balance. 

This oil often replaces the oil from Pimpinella in medicinal prepa- 
rations, but because of the amount in which it occurs and because of the 
modifying influence of the other constituents, no one could assert with 
any certainty as to the identity of the oil in any given mixture. 

The chief use of these oils is for flavoring purposes, and as this character- 
istic is largely due to the anethol it matters little which one is present. 

Fennel Oil 

Fennel oils vary in their composition and consequently in their odor 
and flavor, but the ordinary oil of commerce contains from 50-60 per cent 
of anethol, fenchone, d-pinene, dipentene, and possibly other constituents. 
It is a colorless or slightly yellow liquid with a characteristic odor and 
taste, and solidification point of +3 to +6° C, rotation +12 to +24°- 
This oil comes from Lutzen, Roumania, Moravia, and Galicia. 






930 ORGANIC SUBSTANCES 

Sweet or Roman fennel oil solidifies +10 to +12°, rotation +7 to 
+ 16°. Macedonian fennel oil solidifies +7 to +12°, rotation +5 to 
+ 12°. Both these oils contain no fenchone. 

Indian fennel oil contains both anethol and fenchone, melting-point 
+8°, rotation +21°. 

Japanese oil contains the characteristic constituents, solidifies +7°, 
rotation +10 to +16°. 

Wild bitter fennel oil of France, Spain, and Algiers rotates +48° and 
consists principally of a terpene. 

Caraway Oil 

Caraway oil is a colorless, highly refractive liquid, becoming yellowish 
in time, with a characteristic odor and spicy taste. Its rotation is +70 
to +80°. It is composed of carvone and d-limonene in about equal parts, 
and the carvone may be readily determined by the method described on 
page 607. 

Coriander Oil 

Oil of coriander is a colorless or slightly yellow liquid, rotating +8 
to +13° and soluble in 3 parts of 70 per cent alcohol. It contains d- 
linalool (coriandrol) and about 5 per cent of d-pinene with other constit- 
uents to which the characteristic flavor is due. It is often adulterated 
with turpentine and orange oil, both of which modify the rotation and the 
rotatory power. 

Sandal-wood Oil 

There are several species of Santalum which yield oils, but the oil 
used for medicinal purposes is obtained from the wood of S. album, a 
medium-sized tree growing in India. The oil was formerly distilled in 
the East in large quantities, but owing to the fact that it was almost 
impossible to prevent adulteration, the users of the drug finally adopted 
the expedient of importing the wood and distilling their own oil. At the 
present time all pharmaceutical manufacturers of any pretensions have 
their own plants for distilling sandal-wood oil. 

The oil is used principally for venereal diseases, and is dispensed in 
soluble elastic capsules either by itself or combined with copaiba oil or 
oleoresin cubeb, oleoresin matico, creosote, eucalyptol, salol, pepsin, oleo- 
resin saw palmetto, methylene blue, or cinnamom oil. Pill and tablet 
formulas contain the same remedial agents, also ferrous sulphate, turpen- 
tine and methyl salicylate. 

Oil sandal-wood or an extract is combined with saw palmetto and corn 
silk in elixirs of the sanmetto type. 



OILS 931 

The medicinal value of this drug is due to the santalol content, which 
according to our standard should be no lower than 90 per cent. 

The santalol is determined in the same way that menthol is determined 
in peppermint oil, page 557. The formula for calculating the percentage 
follows : 

AX11. 11 



PerCent 



B- (AX 0.021) 



A is the difference between the number of mils of N/2 sulphuric acid 
required in the titration and the number of mils of N/2 alcoholic potash 
originally taken; and B is the weight of acetylized oil taken. 

Nelson * has described a procedure for the identification of some of 
the volatile oils more commonly occurring in medicinal preparations. 

In case volatile oils are used merely as flavoring agents their identi- 
fication is not so important, and they will be present in small quantity. 
But if used for their medicinal or antiseptic effect it will be desirable to 
obtain as large an amount as possible for the examination. A liberal 
sample of the preparation, neutralized if acid or alkaline, is submitted to 
steam distillation and the undissolved oily layer separated from the dis- 
tillate. 

The physical constants of the volatile oil mixture are first determined. 
The density is taken with a small Sprengel tube. The optical rotation 
and index of refraction are determined, and the boiling temperature is 
taken, keeping the fractions separate for each 10° difference and noting 
the amount and odor of each fraction. This will often afford a clue to 
the nature of the mixture and perhaps direct attention to some of the com- 
ponents. 

Aldehydes (and some Ketones) 

Separation. — The oil (or a suitable fraction) is shaken with an equal 
volume of a saturated solution of sodium hydrogen sulphite in a separatory 
funnel and allowed to stand with occasional shaking for from eight to 
twelve hours. If crystals separate they are filtered off; the aqueous 
layer is separated and the crystals added. To this solution add sufficient 
sodium carbonate to neutralize the acid sulphite, and distill with steam. 
Aldehydes will pass over into the distillate and will usually be recognized 
by their odor. 

Benzaldehyde will indicate oil of bitter almonds; cinnamic aldehyde, 
oil of cassia; pulegone, oil of pennyroyal; methyl nonylketone, oil of rue; 
thujone, oils of tansy, wormwood, or sage. (The last three are ketones 
which react like aldehydes with sodium hydrogen sulphite.) 

1 J. Amer. Pharm. Assn., 6, 1917, 543. 



932 ORGANIC SUBSTANCES 

Aldehydes: Identification 

Benzaldehyde: Liquid, b.p. 733 mm. 177°; d. 15°/15°, 1.050-1.055; 
m.p. of semicarbazone, 214°; easily oxidized to benzoic acid. 

Cinnamic aldehyde: Liquid, b.p. 252°; di5°, 1.054-1 058; m.p. of 
semicarbazone, 208°; oxidized by cold potassium permanganate to benz- 
aldehyde and benzoic acid. 

Citral: Liquid with lemon-like odor; b.p., 228-229°; m.p. of citryl 
/3-naphtho cinchoninic acid, 200°. 

Aldehydes: Determination 

Aldehydes and certain ketones (pulegone, carvone) can be estimated 
by the neutral sulphite method of Burgess. 1 

A saturated solution of sodium sulphite is prepared, and, if acid, is 
neutralized with a solution of sodium hydrate until a faint pink color is 
permanently maintained with phenolphthalein. To 50 mils of such solu- 
tion 25 mils of the oil are added, and two drops of an alcoholic solution of 
phenolphthalein. The whole is then heated on a water-bath to nearly 
boiling-point, constantly shaking. A deep-red color almost at once 
appears, which shows that the action has commenced. A few drops of 
sulphurous acid are then cautiously added, and this is continued until no 
further color is produced after a further addition of SO2. The oil is then 
measured. The obvious advantage of this method is that the end of 
the reaction may be ascertained to a certainty, while the above bisulphite 
method depends on the continual shaking for a period of not less than 
one hour. 

Phenols: Separation 

The oil left in the separatory funnel after treatment with sodium 
hydrogen sulphite, is shaken with two or three times its volume of a 5 per 
cent solution of potassium hydroxide. After the undissolved oil has 
separated the aqueous layer is filtered through a wet filter and a slight 
excess of dilute nydrochloric acid is added. A turbidity at this point will 
indicate the presence of phenols. Methyl salicylate separates with the 
phenols. 

If the odor indicates the presence of methyl salicylate take up the sepa- 
rated phenols in a little ether; separate th^. ether solution and transfer 
it to a small flask ; add from 5 to 10 mils of 5 per cent potassium hydroxide 
solution and warm on a water-bath under a reflux condenser to saponify 
the ester. Then pass in carbon dioxide to saturation and extract the 
1 J. Soc. Chem. Ind., 1901, 1179. 



OILS 933 

phenols (free from methyl salicylate) with ether. Acidify the aqueous 
solution and extract with ether; if methyl salicylate is present a residue 
of salicylic acid will be left on evaporating the ether, which can be identi- 
fied by its melting-point and by the violet color its solutions give when 
treated with ferric chloride solution. 

If methyl salicylate is not present the saponification is omitted. Evapo- 
rate the ethereal solution containing phenols at room temperature. The 
phenols which may be encountered include thymol and carvacrol (from 
oil of thyme), eugenol (from oil of cloves), and diosphenol (from oil of 
buchu). Observe whether the separated phenol shows any tendency to 
crystallize (thymol, diosphenol). Thymol and diosphenol may be sepa- 
rated from the more " acidic " phenols as follows: Dissolve the mixture 
in 5 per cent potassium hydroxide solution and distill with steam. Thymol 
and diosphenol will come over from the alkaline solution while ordinary 
phenol and most of the eugenol will remain in the distilling flask and can 
be recovered with ether. 

Phenols: Identification 

Thymol: Crystalline, m.p. 50.5-51.5°. Identify by U. S. P. test 
(greenish-blue color on adding one drop each of sulphuric and nitric acids 
to its solution in glacial acetic acid). 

Carvacrol: Liquid isomer of thymol, odor like thymol. 

Diosphenol: Crystalline, m.p. 83°, peculiar minty odor. With alcoholic 
ferric chloride its alcoholic solution gives a dark-green color. Its solutions 
reduce ammoniacal silver nitrate and Fehling's solution. 

Eugenol: Liquid, odor of cloves, m.p. of benzoate, 69-70°. Its alco- 
holic solution gives a blue color with ferric chloride. 

Phenols: Determination 

The shrinkage in volume on shaking a measured quantity of the oil 
with 5 per cent sodium hydroxide solution will indicate the proportion 
of phenols present. 

Ketones: Separation 

The oil remaining after the extraction of aldehydes and phenols is now 
to be used for the separation of ketones. Advantage is taken of the prop- 
erty which ketones have of combining with semicarbazide to form crys- 
talline, more or less difficultly soluble, and difficultly volatile semicar- 
bazones. From \ to 1 gram of semicarbazide hydrochloride and an 
equal amount of sodium acetate are dissolved in the least possible amount 
of water. The oil or its fraction (not over 5 mils) is added and enough 



934 ORGANIC SUBSTANCES 

alcohol is stirred in to give a clear solution. (Some NaCl may be pre- 
cipitated.) 

Let the mixture, which should be in a small stoppered flask, stand 
twelve to twenty-four hours and then dilute with water. If much ketone 
is present the oil which separates will soon crystallize more or less com- 
pletely. If crystals separate, filter. In any event separate the oil, trans- 
fer it to a distilling flask, and distill with steam until the volatile oil is 
removed. If any ketone is present a crop of crystals should now separate 
from the residue left in the distilling flask if it is cooled and shaken. Filter 
off the crystals in a Buchner funnel and unite with any that may have 
separated previous to distillation. 

To recover the ketones from their semicarbazones, transfer the semi- 
carbazones to a saponification flask, reserving a portion for melting-point 
and other determinations. Add from 5 to 10 mils of 25 per cent sulphuric 
acid, stopper the flask, and heat on the steam-bath until the crystals are 
decomposed. If camphor was present alone or in preponderating amount, 
it can be seen sublimed into the neck of the saponification flask. Cool 
and open the flask and note the odor. 

Ketones: Identification 

Carvone: Liquid, from caraway and spearmint oils, b.p. 230-231°; 

m.p. of oxime, 72°. 

Pulegone: Liquid, from oil of pennyroyal, minty odor, b.p. 222-223°; 
m. p. of semicarbazone, 168°. 

Methone: Liquid, from peppermint, pennyroyal, and buchu oils, 
minty odor, b.p. 207-208°; m.p. of semicarbazone, 184°. 

Camphor: Ciystalline, from camphor and rosemary oils, m.p. 175- 
176°; m.p. of semicarbazone, 236-238°; m.p. of oxime, 118-119°. 

Thujone: Liquid, from the oils of thuja, wormwood, tansy and sage, 
peculiar odor like wormwood, b.p. 200-201°; m. p. of thujone semicar- 
bazone, 186-188°; m.p. of a-thuj one semicarbazone, 174-175°. 

Methyl nonyl-ketone: Liquid, from oil of rue, odor like oil of rue, 
b.p. 226°, m.p. +13.5°; m.p. of semicarbazone, 123-124°; m.p. of oxime, 
46-47°. 

Ketones : D etermination 

The total quantity of ketones and aldehydes present can be estimated 
by the hydroxylamine titration method, page 607. 

This method will include those ketones which do not react with sodium 
sulphite or sodium hydrogen sulphite. 



OILS 935 

ALCOHOLS, ESTERS, ETHERS, AND OXIDES 

The volatile oil remaining unacted on by the previous methods of treat- 
ment may contain alcohols (as menthol, sabinol, santalol, borneol, and 
terpineol), esters (as menthyl acetate, and bornyl acetate), and phenol 
ethers (as methyl chavicol, safrol, anethol, and apiol), or oxides (as cineol). 

Previous to the further examination of the oil it should be saponified 
by boiling with an excess of alcoholic potassium hydroxide in order to 
decompose any esters present. The alcoholic solution is then diluted with 
sufficient brine to precipitate the oil completely, and the brine solution can 
be used for the identification of organic acids derived from esters. 

There is no good general method for separating the alcohols as a class, 
and the further examination will therefore be governed by the judgment 
of the analyst as to what alcohols are likely to be present. 

The primary alcohols, such as geraniol, can be separated by the cal- 
cium chloride compounds or as acid phthalic esters, provided they are 
present in sufficient amount (at least 25 per cent of the mixture). 

The conversion of alcohols into esters difficultly volatile with steam 
will be successful in some cases. Thus by heating menthol with benzoic 
anhydride for two hours at 160-170° menthyl benzoate is formed, and by 
distilling the mixture with steam the ester, being less volatile, remains in 
the distilling flask, is separated, and the menthol recovered by saponifying. 
The same method is, of course, applicable to any of the more stable alco- 
hols provided they are esterified under these conditions and give benzoates 
slightly volatile with steam. The identification of the tertiary alcohols is 
even a more difficult matter, as they are more or less dehydrated on heat- 
ing with acid anhydrides, but they are not often encountered in a medici- 
nal preparation. When obtained in fairly pure form the alcohols may 
be characterized by the melting-points of their phenyl urethanes. Sabinol 
is the alcohol occurring in oil of savin, and since this oil is frequently 
employed as an abortifacient it should not be overlooked. The best 
chemical method for identifying sabinol consists in oxidizing it by 
means of potassium permanganate to a-tanacetogen dicarboxylic acid 
(m.p. 140°). 

Safrol may be found in the higher boiling fractions of the oil, its boiling- 
point being 233°. The characteristic odor of safrol will serve to direct 
attention to it, and it can be identified by its oxidation product, a-homo- 
piperonylic acid, which melts at 127-128°. This is obtained by the oxida- 
tion of safrol with potassium permanganate. Another phenol ether which 
may be encountered in medicinal preparations is apiol. This boils at 
294°, and will therefore be found in the last fraction of the oil. Apiol 
has a faint parsley odor. On boiling with alcoholic potassium hydroxide 
apiol is converted into isopapiol, which melts at 55-56°. Tri-brom apiol 



936 ORGANIC SUBSTANCES 

melts at 88-89°. Unless present in relatively large amount its identi- 
fication, on acccount of its faint odor, is very difficult. 

Cineol (b.p. 175°) is separated in the first fractions of the oil. Its 
odor, which suggests eucalyptus oil, may direct attention to it if there is 
not too much interfering material. Cineol is an important constituent 
of eucalyptus and cajuput oils and is often used in medicine in pure form, 
being more commonly known as eucalyptol. 

It combines with phosphoric or arsenic acid giving unstable crystalline 
compounds from which cineol can be recovered by adding warm water. 
Its iodole compound (m.p. 112°) is characteristic, but rather difficult to 
prepare from impure cineol. 

Sulphur Compounds, Mustard Oils 

The esters of isothiocyanic acid, characterized by their penetrating 
odor, constitute a special group of sulphur compounds. 

Volatile mustard oil obtained from black mustard, Brassica nigra, is 
mainly allylisothiocyanate, and as this boils at 151° it will be found in 
the first fraction of the oil and will be recognized by its pungent odor. 



Part V 
INORGANIC SECTION 



CHAPTER XXV 
METHODS OF IDENTIFICATION 

The inorganic substances used in the formulas of medicines and phar- 
maceutical preparations are chiefly salts of ammonium, the alkali metals; 
of the alkaline earth group with the exception of barium; aluminum, iron, 
manganese, zinc, cerium, bismuth, lead, mercury, silver, gold, copper, 
antimony and arsenic. The inorganic acids combined in these salts include 
sulphuric, carbonic, sulphurous, thiosulphuric, phosphoric, phosphorous, 
hypophosphorous, boric, iodic, hydrofluoric, hydrochloric, hydrobromic, 
hydriodic, hydrocyanic, hydrogen sulphide, nitric, nitrous, arsenous, 
chloric, and permanganic. The organic acids will be acetic, citric, and 
tartaric. Elemental sulphur, carbon, iodin, phosphorus, iron, and mercury 
are often employed. In addition to the above there are a number of 
double salts of inorganic and organic bases with organic acids, and of 
inorganic bases with organic acids. 

In testing for any of the chemicals which are included in this group 
the worker may follow some wellrecognized scheme of qualitative analysis 
such as that detailed by Newth in his " Manual of Chemical Analysis," 
Noyes' " Qualitative Chemical Analysis," or Fresenius. 

In my work " The Qualitative Analysis of Medicinal Preparations," 
where I outline a general scheme for the separation of the components of 
a complex medicine, I show the distribution of both the inorganic and 
organic substances when the sample is subjected to alcoholic extraction, 
and the subsequent effect of water on the two large fractions obtained by 
the alcoholic treatment. 

Any procedure for analyzing medicine which recommends a preliminary 
ashing of the sample should be condemned by the analyst. Such treat- 
ment will destroy many valuable constituents and materially alter the 
condition of others. On the other hand, it is of course recognized that 

937 



938 INORGANIC SECTION 

organic substances often obscure and prevent the characteristic reactions 
which are essential for the recognition of inorganic substances. For a 
detailed account of what to do and how to proceed with the complete 
qualitative analysis of a complex mixture the worker can refer with advan- 
tage to my directions for manipulating an elixir. 



PRELIMINARY OBSERVATIONS ON RECOGNIZING INORGANIC 
CONSTITUENTS 

The principal inorganic substances or salts of inorganic bases with 
organic acids used in medicine which are insoluble in water are iodin, 
mercuric iodide, phosphorus, sublimed sulphur, iron valerinate, bismuth 
subnitrate, subcarbonate, citrate, and subgailate, cerium oxalate, calcium 
fluoride, reduced iron, charcoal, red and yellow mercuric oxide, mercurous 
iodide, mercurous chloride, precipitated sulphur, zinc carbonate, oxide 
and phosphate, magnesium oxide and carbonate, and a few organic com- 
pounds of bismuth, aluminum, calcium, and iron. The first three men- 
tioned are of course soluble in alcohol. 

In addition to these a medicinal compound may contain calcium car- 
bonate, sulphate or phosphate, ignited oxides of iron and aluminum, talc, 
clay, and siliceous compounds, and possibly other heavy inert salts which 
take part in the architecture of the sample. 

Of the above substances, all are soluble in hydrochloric acid except 
iodin, phosphorus, sulphur, charcoal, calcium fluoride, mercurous iodide, 
mercurous chloride, ignited oxides of iron and aluminum, talc, and clay. 
Mercuric iodide does not dissolve in dilute hydrochloric acid, but it goes 
into solution with the warm concentrated acid. Mercurous chloride is 
converted into mercuric chloride by aqua regia, mercurous iodide is dis- 
solved, sulphur and phosphorus partly oxidized, and some of the oxides 
of iron and aluminum dissolved. The organic compounds will be decom- 
posed to a greater or less degree by boiling with the acids and the metals 
will be found in both the hydrochloric and aqua regia fractions. 

The analyst should note carefully any gases evolved, when the unknown 
product is treated with hydrochloric acid. The carbonates will of course 
give off carbon dioxide, and if zinc phosphide is present, hydrogen phos- 
phide with its characteristic odor and inflammability will be apparent. 

The commoner substances other than those we have already mentioned, 
which are insoluble in water and acids, are the sulphates of barium, stron- 
tium, and lead, the silver haloids, silver, and iron cyanides and tin oxide. 
Their presence in medicinal products would be most unusual. 

In examining the residue insoluble in acids, the presence of free sul- 
phur and charcoal is noted without difficulty. Iodin, unless in large 
amount, will probably have been dissipated by boiling, and recognized 



METHODS OF IDENTIFICATION 939 

by the purple vapors evolved. At this point in the well-ordered schemes 
a test is made for lead and silver. The former is found by treating the 
residue with ammonium acetate solution, warming, filtering, and testing 
the filtrate with hydrogen sulphide. If lead is present, as shown by a 
black precipitate, the residue, both in the dish and on the filter, must 
be washed with warm ammonium acetate until there is no reaction for 
lead. The insoluble portion is then tested for silver by warming with 
potassium cyanide solution, filtering and testing the filtrate with hydrogen 
sulphide. If silver is found it must be removed by successive treatments 
with the cyanide reagent. The residue is then washed clean with yellow 
ammonium sulphide, the filtrate tested for tin and the insoluble matter 
on the filter washed with water. 

Sulphur and carbon should then be burned off in a porcelain crucible 
and the residue fused in a platinum crucible with a fusion mixture of sodium 
carbonate 2, potassium carbonate 2, and potassium nitrate 1. After a 
state of quiet fusion has been attained and the mass cooled, it is leached 
out with hot water, and in this solution will be found the acids present 
in the original residue, united to the bases of the flux. Aluminum and 
chromium might also be present in the aqueous solution in the form of 
aluminate and chromate. The basic substances present will go into an 
hydrochloric acid fraction. 

The aqueous solution should be acidified with hydrochloric acid and 
evaporated nearly to dryness in order to convert any silicic acid to insoluble 
silica. A solution obtained by leaching out the silica residue can then be 
tested for sulphates, fluorides, aluminates, and chromates. The hydro- 
chloric acid fraction may contain barium, strontium, calcium, iron, alum- 
inum, and chromium. The separation and identification of these metals 
can be accomplished by following some well-recognized scheme. 



CHAPTER XXVI 
NON-METALS AND THEIR COMPOUNDS 

HYDROGEN. OXYGEN 

Hydrogen is not a remedial agent, and neither its recognition or 
determination are of moment in medicinal analysis. 

Oxygen is used as a revivifier and for prolonging life, and the strength 
of the gas in a cylinder is readily determined by transferring the necessary 
quantity into a gas burette, and then introducing a measured volume into 
the alkaline pyrogallol tube of an Orsat or other gas apparatus and noting 
the amount absorbed by pyrogallol. The solution is made by dissolving 
20 grams in 200 mils of potassium hydroxide solution (3 to 10), 

PEROXIDES 

Hydrogen peroxide, H2O2, is used extensively in medicine, and is now 
an ordinary household article. The metallic peroxides have come into 
vogue during recent years, but their adaptability is much more limited 
than was at first anticipated. 

Hydrogen peroxide is commonly found in the form of a 3 per cent 
solution corresponding to 10 per cent by volume of active oxygen. This 
is the pharmacopceial strength, and is supposed to represent the product 
sold in packages over the retail counter. It is also sold at 30 per cent 
strength under the name Perhydrol. 

The chief uses of hydrogen peroxide solution are for antiseptic, deodo- 
rant, and styptic purposes. It is used in diphtheria, sore throat, eczema, 
whooping cough, and other conditions requiring an antiseptic wash; for 
gonorrhea, wounds, old sores, disagreeable runnings from the nostrils and 
other parts of the body, as a mouth wash and gargle. It is also used hypo- 
dermically in cyanide poisoning. In dentistry it is employed for general 
oral hygiene, as a bleach for the teeth, and for pyorrhea. 

Hydrogen peroxide is used to a considerable extent as a hair bleach, 
and in combination with the phenylene and toluylene diamines in pro- 
prietary hair dyes. 

Hydrogen peroxide will be found in a great many mixtures which are 
recommended for mouth washes, gargles, remedies for pyorrhea, and other 
antiseptic solutions. These preparations often contain other ingredients 
which are incompatible with peroxide, which soon disappears or becomes 

940 



NON-METALS AND THEIR COMPOUNDS 941 

so weak that it has little or no therapeutic value. For instance, an enthusi- 
astic manufacturer will include permanganate, glycerin, alcohol, and hydro- 
gen peroxide in a single mixture, declare them on the label, and then 
wonder why he is prosecuted for misbranding his product. 

Cold creams, claiming to possess valuable properties due to the pres- 
ence of hydrogen peroxide, have been much in vogue, but in most instances 
the amount of the active ingredient is either negligible or absolutely nil. 
Of late some of the manufacturers have been substituting sodium per- 
beroate,and in this way a product is obtained which will yield active oxygen 
when subjected to the peroxide test. 

The market was, at one time, flooded with soaps, tooth powders, and 
pastes featuring a peroxide content, but except in the case of a dry tooth 
powder containing calcium, magnesium, or zinc peroxide, any peroxide 
added is soon changed to a more stable body and the peroxide character- 
istics disappear. 

Hydrogen Peroxide, U. S. P. 

According to the specifications the standard hydrogen peroxide solu- 
tion should contain 3 per cent by weight of H2O2, corresponding to 10 per 
cent by volume of active oxygen. 

The U. S. P. method for determining the amount of hydrogen peroxide 
is as follows : 

Dilute about 2 grams of Solution of Hydrogen Dioxide, accurately 
weighed, with 20 mils of distilled water, then acidulate it with 20 mils of 
diluted sulphuric acid and titrate with N/10 potassium permanganate 
V. S. It shows not less than 3 per cent of H2O2. 

Each mil of N/10 potassium permanganate V. S. used corresponds to 
.0017008 gram of H2O2, or to .0008 gram of oxygen. Each gram of Solu- 
tion of Hydrogen Dioxide corresponds to not less than 17.6 mils of N/10 
potassium permanganate V. S. 

If it is desired to determine the quantity of oxygen the following pro- 
cedure will be found satisfactory : 

The apparatus consists of a 50-mil side-arm distilling-flask closed with 
a perforated rubber stopper, through which the delivery stem of a glass- 
stoppered burette has previously been passed. The side arm of the flask 
is connected to the nitrometer by means of tightly fitting rubber tubing 
of any convenient length and securely wired at each end to prevent leak- 
age. The burette is fastened loosely in a Bunsen clamp in such a manner 
that the burette and flask can be shaken freely on one plane. The nitrom- 
eter is filled with water, the level adjusted, and the determination made 
as follows: Place about 1 gram of finely powdered manganese dioxide 
or potassium permanganate in the side-arm flask and add 10 mils of 10 
per cent sulphuric acid. Dilute 10 mils of the hydrogen peroxide solu- 



942 INORGANIC SECTION 

tion to be tested to 100 mils and place a portion in the burette. After 
sufficient of the solution is run out to fill the delivery stem of the burette 
fit the stopper (with attached burette) snugly into the neck of the generat- 
ing flask, and adjust the level of the water in the nitrometer so as to equalize 
the pressure within the system. Allow 10 mils of the diluted dioxide solu- 
tion to run slowly into the generator through the burette. After shaking 
the flask to liberate the dissolved oxygen as completely as possible again 
adjust the level and note the temperature and pressure. A correction 
of 10 mils (the volume of solution run into the generator) is subtracted 
from the reading, and the remainder reduced to 760 mm. pressure and 
20° C. temperature. 

The method recommended in the eighth revision for determining the 
acidity has been the cause of much criticism, and there seems to be no 
good reason for the figures obtained by an indirect titration. Warren, 
Kebler and Ruddiman, 1 who made an exhaustive study of commercial 
peroxides, state: 

" Numerous experiments have been made on the determination of the 
acidity of hydrogen peroxide solutions by the pharmacopoeial and other 
methods, and it has been found that methyl orange could be substituted 
with advantage for phenolphthalein if the present pharmacopoeial method 
is retained. Experience and experiments furthermore show that the free 
acidity can readily be determined by direct titration, using phenolphthalein 
as indicator, and there seems to be no good reason for continuing the use 
of the present pharmacopoeial method." 

It is only necessary to add to 25 mils of the hydrogen peroxide about 
5 or 6 drops of phenolphthalein test solution (U. S. P.) and titrate directly 
with N/10 alkali to the development of a light-pink color. Under the 
conditions this method is accurate to .1 to .2 mil. For practical pur- 
poses the test in the Pharmacopoeia should be stated as follows: 

If to 25 mils of the solution of hydrogen peroxide 5 or 6 drops of phenol- 
phthalein test solution are added, not more than 2.5 mils N/10 KOH 
should be required to produce a pink color (limit of free acid). 

Acetanilid is often used as a preservative, but the amount is small, 
usually about .1 per cent. This, of course, must be declared on the label 
and in order to determine the correctness of the declaration the following 
method may be employed: 

In a side-neck flask of 200-mils capacity, place about half a stick of 
caustic potash or soda (6 to 7 grams). Add about 20 mils of water to 
dissolve, and then 25 to 30 grams of granulated metallic zinc (the zinc had 
best be in as fine particles as can be obtained in " granulated " form. 
There is reason, however, to believe that " zinc dust " is too finely divided 
for this purpose). Then add a measured amount (not over 50 mils) of 
UJ. S. Dept. Agri. Bur. Chem Bull. 150, 5. 



NON-METALS AND THEIR COMPOUNDS 943 

the solution to be tested. Connect the flask, on the one side with a flask 
to supply steam, arranging the tube to deliver steam near the bottom of 
the solution ; connect on the other side with a condenser. The condenser 
should deliver into a Peligot bulb tube or some other arrangement by 
which the distillate is immediately brought in contact with moderately 
strong hydrochloric acid. 

Raise the heat on the flask, slowly, and when nearly half of the contents 
have distilled over, start the steam passing through. The end of the 
distillation is a matter of guess. When the anilin is coming over in 
quantity, fumes are to be seen in the receiver, but for the last portions 
they cannot be seen. When it is judged that all has come over, detach 
the receiver and catch what comes over later in a fresh receiver or a 
beaker, and titrate it separately. 

In conducting the titration, standard bromide-br ornate reagent is run 
in from a burette until a faint yellow coloration remains, rotating the flask 
sufficiently to agglomerate the precipitated tribromanilin. 

To prepare the volumetric bromin solution, dissolve 25 grams of caustic 
potash in 20 to 40 mils of water, cool, and add liquid bromin until it 
appears supersaturated. Then dilute to about 200 mils and boil out 
excess of bromin (judged by the color). Cool, and dilute to 1 liter. 
This should give a solution of which 1 mil = nearly .01 gram acetanilid. 
Standardize by means of a solution containing .5 gram acetanilid in 
200 mils of water, using 30- to 50-mil lots at a time, treated either by dis- 
tillation in the manner above given, or by boiling with strong hydro- 
chloric acid. Either method was found to give the same result with the 
same amount of acetanilid. 

The detection of Irydrogen peroxide or a peroxide in admixture with 
other drugs is not difficult, but their determination usually presents con- 
siderable difficulty, and quantitative methods are still in the experimental 
stage. 

There are three tests for detecting hydrogen peroxide which deserve 
special mention. 

1. An aqueous solution of hydrogen peroxide, even at considerable 
dilution, will turn a deep-blue color when treated with a few drops of a 
dilute solution of potassium chlorate followed by a few drops of dilute 
sulphuric acid, and on shaking with ether the blue color will dissolve in 
part and color the ether for some time. If the quantity is small the ether 
should be free from alcohol. This test is not as delicate as some others, 
but it will show a quantity considerably less than the minimum amount 
that has any excuse for existing in a product which depends on peroxide 
for its activity. 

2. An aqueous solution of hydrogen peroxide treated with potassium 
iodide solution and rendered slightly acid with dilute sulphuric acid 



944 INORGANIC SECTION 

becomes yellow, and on shaking with chloroform, the solvent becomes 
violet owing to the absorption of iodin. This test is probably more deli- 
cate than the preceding, and in some instances the color will appear only 
on long standing. 

3. Probably the most delicate test is that with titanium sulphate (1 
mg. Ti02 to 1 mil). A few mils of this reagent are added to the aqueous 
solution followed by a little dilute sulphuric acid. Hydrogen peroxide 
gives a yellow color, the shades depending on the quantity present. This 
test is extremely delicate, and if negative proves beyond a doubt that 
hydrogen peroxide is absent. A positive test ought always to be supple- 
mented b3^ the two others given above, because the influence of various 
other organic substances has not yet been determined. This test is of 
course the reverse of the one used for determining titanium in steel. 

In testing for peroxides in liquids, the volatile substances other than 
water should be evaporated, any acids neutralized with dilute alkali and 
the solution again made acid with dilute sulphuric, filtering from any pre- 
cipitate that may have formed. The solution should then be subjected 
to the three tests given above. 

Soaps, cold creams, and tooth pastes are tested as follows : The sample 
is thoroughly macerated with water and transferred to a Squibb separator 
of 16 oz. capacity, where it is treated with a slight excess of dilute sulphuric 
acid. As soon as separation occurs, the clear liquid is filtered into another 
separator, the magma shaken up with distilled water and the washings 
filtered into the second separator. This procedure is then repeated and 
the clear liquid can then be subjected to the above tests. 

Tooth powders can be handled in practically the same way. The 
precipitate will consist in large part of calcium sulphate, but this will 
remain behind on the filter. 

Assay of Metallic Peroxides 

One-tenth to three-tenths gram of the material is weighed into a flask, 
treated with 50 mils of water and 20 mils of dilute sulphuric acid (hydro- 
chloric acid in the case of calcium peroxide), and then titrated with N/10 
permanganate. 

In the case of sodium peroxide use 1 to 1.5 gram and add gradually 
to 950 mils of 1 per cent sulphuric acid, making up to 1000 mils with water; 
100-mil portions are used for titration. 

1 mil N/10 potassuim permanganate = .0036 gram Ca0 2 

= .002 gram Mg0 2 
= .003786 gram Na 2 2 
= .0061 gram Sr0 2 
= .0048 gram Zn0 2 



NON-METALS AND THEIR COMPOUNDS 945 

NITROGEN AND ITS ACIDS 

Nitrogen as a free element is of no moment in our work, but its identi- 
fication, as one of the elements in an organic compound, is of considerable 
importance, and in some instances where a new and totally unfamiliar sub- 
stance is under examination, its determination will be necessary. The 
methods for detecting and estimating the percentage of nitrogen in organic 
compounds are fully described in Gattermann's " Practical Methods of 
Organic Chemistry," to which the worker is referred. 

Nitrogen Oxyacids 

Nitrate of potassium and nitrate of silver are the two salts of nitric 
acid which have an important place in medicine. The former is a diuretic, 
and the latter an antiseptic and astringent. The estimation of nitrates 
follows more conveniently from the determination of the metallic element. 

The alkali nitrates have a limited use in therapeutics, and amyl and 
ethyl nitrite, the latter in sweet spirit of nitre, are of considerable impor- 
tance. The method of determining the nitrite radicle and estimation of 
the ester has already been given in detail on page 734. 

Nitrites may be determined by titration with permanganate accord- 
ing to the equation 5HN02+K2Mn20 8 +3H 2 S04 = 5HN03+K 2 S04+ 
2MnS04+3H20. If the reagent is standardized with iron, 4 atoms of 
iron correspond to 1 molecule of N2O3. For 1 part NO2 at least 5000 parts 
of water should be present. The sample is dissolved in water slightly 
acidulated with sulphuric acid, the permanganate added till the oxidation 
of the nitrous acid is nearly completed, the solution then made strongly 
acid and finally permanganate is added to light-red coloration. 

THE HALOGENS AND HALOGEN ACIDS 

With the exception of iodin, none of these elements by themselves 
have an extended application in medicine. Bromin water and chlorin 
water are preparations used to a slight extent where drastic disinfectants 
are needed, such as in cancerous conditions, foul discharges, boils, and 
ulcers, smallpox, diphtheria, and venereal disease. 

The use of iodin is on the increase. It is a popular application in 
dentistry and nose and throat work, where it functionates as an anti- 
septic and cleansing agent, and possibly as a tonic. It is used in erysipelas 
and other skin diseases, in enlarged and scrofulous glands, venereal dis- 
charges, and in many other conditions requiring an antiseptic. 

The official liquid preparations of iodin are the tincture, which contains 
70 grams of iodin and 50 grams of potassium iodide in 100 mils of alcohol 



946 INORGANIC SECTION 

(95 per cent), and the compound solution, containing 5 grams of iodin and 
10 grams of potassium iodide in 100 mils of water. These preparations 
are often too irritating to the membrane to be used without modification, 
and hence will be diluted with water or glycerin. Inhalants are made up 
with a neutral oil base containing different percentages of iodin sometimes 
up to 2 per cent, with menthol, thymol, eucalyptol, camphor oil of cassia, 
sassafras, etc. 

Besides the above-mentioned common methods of dispensing iodin 
in solution, preparations have recently appeared which contain no iodides 
or glycerin, but which depend upon hydriodic acid and alcohol to keep the 
iodin in solution. These solutions are capable of considerable dilution 
without the precipitation of iodin. 

Iodin ointments are popular. The iodin is usually dissolved in gly- 
cerin and potassium iodide, and then mixed with the base. Ammonium 
oleate mixes readily with iodin and glycerin and ammonium iodide, 
and proprietary preparations containing these substances in a petrolatum 
base are widely exploited. 

Bromin chloride, BrCl, is a reddish-yellow, mobile, volatile liquid, 
unstable, losing chlorin at 10°. It has been used in cancerous conditions. 
Iodin monobromide, IBr, and monochloride, IC1, are solids. Iodin penta- 
bromide, IB15, and tribromide, IBr3, are dark-brown liquids which are 
employed in dilute spraj^s for diphtheria and other conditions requiring 
an antiseptic application to the mucous membrane. 

Characteristics and Qualitative Tests for Elementary Halogens. — 
Chlorin is well known as a greenish-yellow gas, with a characteristic 
suffocating odor, and an irritating action on the mucous membrane of 
the nose and throat. Its solution in water is yellow in color and the addi- 
tion of a bromide or an iodide, bromin or iodin are liberated, and will 
dissolve in chloroform with their characteristic color. Chlorin water 
is a powerful bleaching agent and will decolorize indigo solutions. 

Bromin is a dark, brownish red, volatile liquid, vaporizing at the ordi- 
nary temperature. Its action on the membrane of the nose and throat 
and eyes is powerful, but the effect may be ameliorated by exposing the 
inflamed parts to the vapors of chloroform. Its bleaching action is less 
than that of chlorin. It gives a yellow color with starch and its aqueous 
solution is reddish. It dissolves in chloroform with a reddish-brown color 
and will liberate iodin from solutions of iodides. 

Iodin is a solid, steel-like, and shiny in appearance, and readily passes 
into a deep violet -colored vapor at ordinary temperature, and on heating. 
It fuses, but will volatilize without melting. It is only slightly soluble 
in water, but dissolves readily in alcohol and other organic solvents, 
hydriodic acid, and iodide solutions. Its solution in chloroform is violet 
deep-purple or almost black, depending on the quantity present. With 



NON-METALS AND THEIR COMPOUNDS 947 

cold starch paste iodin gives an intense indigo-blue color which will dis- 
appear on heating and again appear on cooling. 

Quantitative Analysis of Preparations Containing the Free Halo- 
gens. — Iodin can be titrated directly with N/10 thiosulphate, using starch 
as an indicator. 

For assaying tincture of iodin the Pharmacopoeia method recommends 
using 5 mils, mixed with 25 mils of water, which will require about 27.25 
mils N/10 thiosulphate for decolorization. 

The compound solution of iodin is assayed by weighing 6.3 grams 
and titrating with the same reagent, which should require about 24.75 mils. 

1 mil N/10 Na 2 S 2 3 = .01259 gram iodin 

In making an assay of the more common iodin mixtures the procedure 
will depend somewhat upon the nature of the ingredients, which will 
have to be identified by a previous qualitative examination. The direc- 
tions here given can be used for a mixture containing free iodin, free 
hydriodic acid, an iodide, alcohol, and water. Glycerin will not inter- 
fere with the tests, but no satisfactory method is available for its own 
estimation except in an approximate manner, and the analyst is referred 
to that portion of the work which discusses glycerin specifically. 

If desired a weighed quantity can be made up to a definite volume 
ctnd aliquots taken for the tests. If the specific gravity is. determined 
and measurements made at the same temperature the sample may be 
measured. Twenty-five mils are transferred to a 100-mil graduated flask 
and made up to the mark. An aliquot amounting to 25 mils is titrated 
with thiosulphate in order to determine the free iodin, and in the decolor- 
ized solution any free hydriodic acid is determined by titrating with N/10 
alkali. 1 mil N/10 KOH = . 012690 HI. A second aliquot of 25 mils is 
transferred to a separatory funnel, diluted with water and shaken out 
with chloroform, if the iodin fails to entirely leave the aqueous liquid, 
collect the chloroform in another separatory funnel and repeat until 
decolorized. Combine the solvents and wash with water, discarding sol- 
vent and returning wash water to the main liquid. Filter and wash. 
Then neutralize filtrate and washings and concentrate over the steam-bath. 
Filter if not clear and in the filtrate determine the iodin by precipitating 
with silver nitrate in the presence of dilute nitric acid. Collect the silver 
iodide on a tared Gooch, wash thoroughly and weigh. From the total 
iodin found deduct that due to hydriodic acid and calculate the rest to 
the iodide salt present. Alcohol must be determined in a separate portion 
of the original sample. In order to do this proceed as directed for the 
determination of alcohol in galenical mixtures, page 2, first destroying 
the free iodin with crystalline thiosulphate and then neutralizing any free 
acid. 



948 INORGANIC SECTION 

Free iodin in ointments and inhalants of an oily nature can be deter- 
mined by transferring the weighed sample to a flask possessing a ground- 
glass stopper and a long air condenser. Alcohol containing 10 per cent 
potassium iodide is then added and the flask warmed until the ointment 
has melted, and then gently agitated. If the heat tends to drive the iodin 
beyond the lower half of the air cooler, introduce a little aqueous potas- 
sium iodide through the cooler and continue the agitation. Cool, remove 
the stopper, and transfer alcoholic liquid to a closed flask, washing out 
flask and residue with alcohol containing potassium iodide. Repeat 
digestion with alcoholic potassium iodide and then wash out condenser 
and titrate the solution with N/10 thiosulphate. 

While the determination in medicinal preparations of free chlorin or 
bromin is seldom a matter of moment, this may be accomplished by 
adding an excess of potassium iodide solution and titrating the liberated 
iodin with thiosulphate. - Each mil 

N/10 Na 2 S 2 3 = .007936 gram Br 
= .003518 gram CI. 

Sulphur Iodide. U. S. P. Assay. — .5 gram of finely pulverized sulphur 
iodide together with 1 gram potassium iodide is dissolved in 20 mils of 
water (sulphur separating), not less than 28 mils N/10 Na2S2C>3 should 
be required for complete decolorization of the mixture using starch as 
indicator. 

Assay of Iodin Ointment, L. H. Freed. 1 — Free Iodin. — Carefully clean, 
dry, and tare a 120-mil Erlenmeyer glass-stoppered flask and accurately 
weigh into it from 3 to 5 grams of ointment, using a glass rod for trans- 
ferring it. Add 30 mils chloroform, shake the flask a few minutes until 
the ointment is apparently dissolved. Then add 30 mils of distilled water, 
shake, and immediately titrate with N/10 sodium thiosulphate. 

Potassium Iodide. — Five grams are weighed into an ordinary 250-mil 
Erlenmeyer flask and attached to a distillation apparatus, using as a 
receiver a 250-mil glass-stoppered Erlenmeyer containing 1 gram potas- 
sium iodide dissolved in 30 mils distilled water, and 30 mils chloroform. 
Allow the end of the condenser tube to dip into this mixture. Make all 
connections air-tight, using rubber stoppers. Mix 5 mils sulphuric acid 
with 150 mils of distilled water; add the acid mixture quickly into the 
flask followed by a few pieces of pumice which have previously been heated 
to redness and dropped into cold water. Finally, add about 5 grams of 
ferric alum. Place upon a wire gauze and apply direct flame very slowly 
at first, until the purple vapors of iodin have all distilled over. The 
1 J. Amer. Pharm. Assn., 1915, 4, 621. 



NON-METALS AND THEIR COMPOUNDS 949 

lodin will sometimes condense in the tube and not go down into the receiv- 
ing flask; if this happens move the flame and allow the liquid to run back 
into the tube and dissolve the iodin. Replace the flame and continue 
distillation until an oily substance comes over. Discontinue the dis- 
tillation by first removing the receiving flask, then remove the flame and 
wash out condenser tube end with 20 mils water. Immediately titrate 
with N/10 thiosulphate. The result is the total iodin, from which, after 
subtracting the amount of free iodin, the quantity of potassium iodide 
is calculated. i 

Rapid Method for Separation and Estimation of Iodin. — This method, 
discovered by Seeker and Mathewson, 1 was first used for estimating iodin 
in Erythrosine, but it is applicable to other organic compounds, and useful 
in assaying iodin in inorganic mixtures containing chlorin and bromin. 
Dissolve .3 to .4 gram of the sample in 5 mils 10 per cent sodium hydroxide, 
add 35 mils 7 per cent, potassium permanganate, cover with a watch-glass 
and add 10 mils concentrated nitric acid. Heat on a steam-bath, keeping 
covered until ail spattering ceases, then remove cover and evaporate to 
dryness. Treat the residue with 5 mils permanganate and 5 mils nitric 
acid, and again evaporate. Dissolve the residue in 50 mils water, 5 mils 
nitric acid, and 40 mils saturated sulphur dioxide solution. Then add 
excess silver nitrate, boil till sulphur dioxide is expelled, and the silver 
iodide has flocculated, and filter and weigh the latter as usual. 

HALOGEN ACIDS 

Of considerably greater importance in medicine than the elemental 
halogens themselves are the halogen acids, and more particularly the salts 
of these acids. There are two general classes of these acids, halogen 
hydrides and halogen oxyacids. 

To the first belong hydrochloric, hydrobromic, hydriodic, and hydro- 
fluoric acids. The free acids, with the exception of hydrofluoric, which 
boils at 19.5° C, are fuming gases at the ordinary temperature. They 
dissolve readily in water, and their solutions constitute the different grades 
and strengths of acids of commerce. Many of the salts of the first three 
are well-known remedies and they will often be found in the analysis of 
complex mixtures. The identification of these acids has already been 
discussed in the general scheme for arriving at the composition of the 
inorganic constituents of a given product. 

Hydrochloric acid of the U. S. P. is an aqueous solution of about 31.5 to 

32 per cent HC1 gas. Diluted it may be used as an antiseptic, antipyretic, 

and caustic in fevers, dyspepsia, syphilis, eczema, psoriasis, etc. As a 

popular remedy it should be anticipated in preparations recommended 

1 U. S. Dept. Agri. Bu. Chem. Circ, 65. 



950 INORGANIC SECTION 

for impaired digestion, and it will sometimes be found accompanying all 
of the digestives and stomachics in tablets and liquid preparations. Chlor- 
ides of the different metals find application over the entire field of medicine. 

Hydrobromic acid is marketed in different strengths, but the official 
acid is the dilute, and contains 10 per cent by weight of HBr. It has a 
limited use in allaying nervous conditions, especially of an acute or violent 
nature. The bromides are much more stable and are extensively used 
in medicine. 

Hydriodic acid is official in the Pharmacopoeia as a 10 per cent 
solution, but acid of much greater strength is obtainable. If made accord- 
ing to the specifications of the standard, the solution will contain a small 
quantity of hypophosphorus acid and perhaps a little tartaric acid. Its 
chief use is for the preparation of syrup hydriodic acid, which contains 
about 1 per cent by weight of HI. 

Hydriodic acid is used in rheumatism, bronchitis, asthma, syphilis, 
obesity, psoriasis, eliminating mercury and arsenic from the system, and 
as a tonic. The metallic iodides are in the aggregate probably the most 
extensively used chemicals in the field of medicine. Potassium iodide 
will be found in many of the advertised asthma and hay fever " cures " 
and in the sarsaparillas. 

Quantitative Estimation of the Free Acids and Acid Radicles. — The 
estimation of free hydrochloric acid in aqueous solution may be accom- 
plished by titrating with standard alkali, and the other halogen acids can 
also be determined in like manner. 

The Pharmacopoeia does not direct that either hydrobromic or hydri- 
odic acid shall be titrated directly with alkali. The former is determined 
after neutralizing with ammonia, by titrating with silver nitrate, and the 
latter by an indirect method detailed below. 

For determining the quantity of halogen in a mixture containing the 
free acids or an aqueous solution of a chloride, bromide, or iodide, there is 
no better method than that of precipitating with silver nitrate in presence 
of an excess of dilute nitric acid, boiling, filtering onto a tared Gooch, 
and weighing the silver compound. The details of this manipulation are 
well known to a worker in quantitative methods. It is applicable to com- 
plex medicines, and may be employed after the removal of organic sub- 
stances by shaking out procedures, provided, of course, that no halogen 
acid or compound has been introduced during the manipulation. Before 
precipitating with silver nitrate the solution should be boiled for ten to 
fifteen minutes after the addition of concentrated nitric acid. The 
quantity of the acid added should not be great enough to cause a decom- 
position of any iodide or bromide. After boiling, the silver nitrate is 
added, and when the precipitate has agglomerated, it is filtered onto a 
tared Gooch and well washed with water and finally with alcohol to remove 



NON-METALS AND THEIR COMPOUNDS 



951 



organic products of decomposition. From the weight of the silver com- 
pound the acid or salt can be readily calculated. 

The determination of the purity of a salt of a halogen acid by the 
U. S. P. method may be accomplished as follows. 

A weighed amount of the salt is dissolved in water, the solution treated 
with 2 to 3 drops of potassium chromate, and then titrated with N/10 
silver nitrate until a permanent brownish-red color is obtained. 

This procedure as applied to the following salts may be summarized. 





Amount 
Taken, 
Grams 


Made up to 


Aliquot 
Mils 


Mils N/10 

AgNOs 


Purity, 
Per 
Cent 


lmilN/10 
AgNOs 
equals 
gram 


HBr 


10 

3 

1 

1 

0.3 

0.5 

0.3 

1 

0.5 

0.5 

0.3 


100 mils neutralize 
100 mils 
100 mils 
100 mils * 

50 mils 

10 mils 

50 mils 
100 mils 

10 mils 

50 mils 

10 mils 


8 

10 
10 
20 
50 
10 
50 
10 
10 
50 
10 


10 
31.6 
18.7 
22.5-23.9 
24.6-25.85 

30-30.8 

28.5-30 

17.05 

33-34.6 

27.4-29.4 

26-26.8 


10 
97 

99.5 

97 
97 
99 
97 
99 
98 
97 
97 




NH 4 Br 

NH 4 C1 

LiBr 


.009729 
.005311 
.008634 


KBr. . 


.011822 


KI 


.016476 


NaBr 

NaCl 

Nal 


.010224 
.005806 
.014878 


SrBr 2 +6H 2 0.. 
ZnBr 


.017647 
.011181 



For hydriodic acid and some of the iodides the Pharmacopoeia 
recommends a different procedure. A weighed quantity in aqueous 
solution is treated with a known excess of N/10 silver nitrate, 5 mils of ferric 
ammonium sulphate test solution and 3 to 4 mils of nitric acid free from 
nitrous fumes. After thorough shaking it is titrated back with N/10 
potassium sulphocyanate until a permanent reddish-brown tint is obtained. 

The application of this method to pharmacopceial chemicals may be 
noted below. 





Amount 






N/10 








Taken, 
Grama 


Made up to 


Aliquot, 
Mil3 


AgN0 3 , 
Mils 


N/10KSCN 


lmilN/10 

AgNOs equals 


HI 


2.54 


50 mils 


50 


25 


not more than 
5 mils 


0.5% HI 


Syrup HI. . . 


31.73 


50 mils 


10 


8 


not over 3 mils 


0.2% HI 


Syrup Fel 2 . . 


10 


100 mils 


15.4 


6 


not over 1 mil 


1.0% Fel, 


SrI 2 +6H 2 0. 


0.5 


100 mils 


100 


25 


1.7-3.1 


Purity 98% 


Znl 2 


0.5 


20 mils 


20 


35 


3.4-4 


Purity 98% 



952 INORGANIC SECTION 

HALOGEN OXYACIDS 

Hypochlorous acid, HCIO, is familiar to the pharmaceutical chemist 
in the form of its calcium salt known as bleaching powder, and in the form 
of a solution of its sodium salt, which is called chlorinated soda or Labar- 
raque's solution. Both of these salts are unstable and readily part with 
their chlorin even under the influence of carbon dioxide. They also 
yield chlorin when treated with dilute acetic and mineral acids, and in 
this way are sharply distinguished from chlorides and chlorates. When 
silver nitrate is added to a solution of sodium hypochlorite there is a pre- 
cipitation of silver chloride representing two-thirds of the silver, the 
balance being dissolved probably as silver chlorate. 

NaOCl+AgNOs = AgClO-f NaN0 3 
3AgC10 = AgC10 3 +2AgCl 

Sodium hypochlorite solution is usually sold unmixed with any other 
drug. The Pharmacopoeia directs that it shall contain not less than 2.4 
per cent available chlorin. The activity may be determined by trans- 
ferring .5 to .7 gram weighed out by means of a dropping bottle to an 
Erlenmeyer flask, diluting with 50 mils of water, adding 2 grams potassium 
iodide and 10 mils hydrochloric acid and titrating the iodin with N/10 
thiosulphate. 

The solution is used chiefly as a disinfectant and antiseptic in cases 
of malignant nature, scarlet fever, typhoid, scrofula, syphilis, and where 
there are foul and offensive discharges. 

Method of Assay of Calcium Hypochlorite, U. S. P.— Introduce into 
a stoppered weighing bottle between 3 and 4 grams of the sample and weigh 
accurately; triturate thoroughly with 50 mils of water and transfer to a 
graduated 1000-mil flask, adding rinsings and make up to volume. After 
shaking allow the sediment to settle and decant 100 mils. Add 1 gram 
KI and 5 mils dilated hydrochloric acid and titrate with N/10 Na2S203. 
Multiply the number of mils consumed by .3518 and divide the product 
by to the weight of the sample ; the quotient represents the percentage 
of available chlorin present. 

The acids, chloric, HCIO3, bromic, HBrC>3 and iodic, HIO3, differ in 
stability in the opposite order to that usually shown by halogen compounds. 
Iodic acid is a comparatively stable solid, but is readily reduced by sulphur 
dioxide or hydrogen sulphide with liberation of iodin, and it reacts with 
hydriodic acid, all of the iodin being set free, HI03+5HI = 3Ii20+3l2. 
This reaction is of value in detecting the presence of an iodate when mixed 
with an iodide, for by dissolving in water and adding acetic acid the liber- 
ated acids react and the iodin is set free. 

The most important medicinal chemical representing this group is 






NON-METALS AND THEIR COMPOUNDS 953 

potassium chlorate. It has an extensive use as a household remedy for 
sore throat and is also used in diphtheria, stomatitis, and diseases of the 
mucous membrane. It will be found in aqueous mixtures intended as a 
spray in nasal troubles, hay fever, asthma, and the like, and mixed with 
opium extract for hemorrhoids. In the powder form it occurs mixed with 
other substances as a dusting mixture for wounds and ulcers. 

Potassium chlorate is often combined with ammonium chloride in 
throat tablets and with sodium chloride in nasal sprays. 

Sodium chlorate is also in general use, and magnesium chlorate has 
a slight use. 

Having detected the presence of a chlorate in the regular scheme of 
analysis, and there being no other halogen acid present, the chlorate may 
be determined by dissolving a weighed sample in water, adding dilute 
sulphuric acid and a piece of zinc and allowing the reaction to continue 
for thirty minutes. The solution is then filtered from any undissolved zinc, 
the filter paper washed and the filtrate neutralized with sodium carbon- 
ate and the chlorin then determined by precipitation with silver nitrate 
in the presence of nitric acid. The amount of KCIO3 may be obtained 
from the factor .8551, NaC10 3 .7445. 

The determination of the chlorides and chlorates in admixture may 
be accomplished by weighing out the sample into a graduated flask, dis- 
solving in water, and determining the chloride in an aliquot by precipi- 
tating with silver nitrate. An aliquot of the same quantity is then treated 
with zinc and sulphuric acid as described above and the total chlorin 
determined. The silver nitrate representing the chlorate is then easily 
figured and calculated to the chlorate. 

Bromates are unimportant medicinally. Iodates of sodium and potas- 
sium are used sometimes both as substitutes for chlorates and iodides. 
They are used externally in trachoma, corneal infiltration, and torpid 
ulcers and internally for acute and chronic muscular rheumatism. 

Iodin pentoxide, I2O5, so-called "Anhydrous Iodic Acid," is a' white 
powder soluble in water with formation of IH2O3. It is used internally 
in gastric hemorrhage and vomitings and externally in nose and throat 
work and venereal disease. It is a powerful oxidizing agent. 

Iodic acid is a colorless crystalline powder soluble in water and used 
medicinally in aqueous solution for the ailments mentioned above. 

Perchloric acid, HCIO4, in the form of its potassium salt is used as an 
antipyretic and antiperiodic in pernicious fevers and malarial conditions. 
The perchlorates are more stable than the chlorates. Sulphuric acid 
liberates the free acid, which is a colorless, fuming, corrosive, volatile 
liquid. No yellow color appears in this test as is the case with chlorates. 
Hydrochloric acid has no action on perchlorates, which is in sharp dis- 
tinction from its action on chlorates. 



954 INORGANIC SECTION 

ORGANIC HALOGEN COMPOUNDS 

Organic compounds of iodin are commonly employed as medicinal 
agents. The iodin in these substances can often be determined by boiling 
a solution of the substance with dilute nitric acid and then precipitating 
with silver nitrate, filtering and thoroughly washing with alcohol and then 
water (see Emery's Method for Determining Iodin in Antipyrin periodide, 
described on p. 801. It often happens that this procedure will not suffice 
to bring the iodin into proper condition for precipitation with silver nitrate 
and in the event of such a contingency recourse must be made to a Carius 
combustion. Again it will be simply necessary to saponify with alcoholic 
potash (ethereal salts), see chloroform and iodoform, p. 742-744. 

The determination of chlorin and bromin in organic combination 
follows the same general procedure. 

SULPHUR AND SULPHUR ACIDS 

The Pharmacopoeia recognizes three forms of sulphur, the sublimed or 
flowers of sulphur, the precipitated or lac sulphur, often impure from the 
presence of calcium salts, and the washed. One of the commonest sul- 
phur preparations is the combination with potassium bitartrate. Sulphur 
is employed in atonic gout, chronic rheumatism, chronic catarrh, asthma, 
piles, and cutaneous affections, and is dispensed usually in the form of 
lozenges and tablets. 

Sulphur is insoluble in water and precipitated sulphur does not dissolve 
in alcohol. Sublimed sulphur is somewhat soluble in alcohol. The iden- 
tity of the element is determined by its burning with a pale-blue flame, 
producing sulphur dioxide, which has a characteristic odor and turns 
potassium iodate starch paper. When heated in a test-tube, sulphur 
melts and boils off as a brownish-yellow vapor, which condenses to brown 
drops on the moderately hot parts of the tube, and as a yellow sublimate 
on the upper and cooler part. Nitric acid oxidizes sulphur to sulphuric 
acid with evolution of nitrogen peroxide. 

When elemental sulphur is combined with substances soluble in water, 
it is readily determined by treating the ground substance with water, 
filtering through a Gooch, drying, and weighing the residual sulphur. 
When sulphur is combined with charcoal or other substances insoluble 
in water or carbon bisulphide, the sample should be ground and extracted 
with carbon bisulphide, the solvent collected in a tared dish, evaporated, 
and the residue weighed. 

Free sulphur in complex formulas containing vegetable drugs can be 
determined by oxidation with nitric acid in a Carius tube. The sample 
should be ground and extracted with hydrochloric acid, filtering through 
a Gooch, and the residue is then transferred to the tube. Sufficient fuming 



NON-METALS AND THEIR COMPOUNDS 955 

nitric acid is added to cover the material, the open end of the tube drawn 
out to a thick-walled capillary and sealed off. The tube is introduced 
into a Carius combustion furnace and heated from four to ten hours, 
raising the temperature gradually from 100 to 300°. After cooling in the 
furnace, the pressure is relieved by applying a flame to the capillary. 
The end of the tube is broken off, the contents washed out, the diluted 
liquid filtered, and the sulphate precipitated by barium chloride. The 
barium sulphate is filtered, washed, ignited, and weighed. 

Hydrogen Sulphide 

Hydrogen sulphide water is occasionally employed as a remedy in 
certain types of tuberculosis. Barium sulphide is a depiliatory and will 
be found mixed with zinc oxide and starch. Sulphurated lime, which 
is a mixture of calcium monosulphide and sulphate, is also used as a depili- 
atory and as an alterative. It will be found in pills and tablets and is 
employed in measles, scarlet fever, erysipelas, influenza, acne, and furun- 
cular eruptions. 

The determination of sulphide sulphur in substances of this nature 
can be made by the method of assay for calcium sulphide in the Pharma- 
copoeia. 

Introduce about .2 gram of calcium sulphide, accurately weighed, 
into a glass-stoppered bottle or flask; add 50 mils of distilled water, mix, 
and quickly introduce 30 mils of a 10 per cent ammonium chloride solu- 
tion and immediately stopper the flask. Agitate the contents for a few 
minutes, add quickly 20 mils of a 10 per cent cadmium chloride solution, 
immediately insert the stopper and again agitate well for a few minutes. 
Then add 5 mils of acetic acid, heat the mixture on a water-bath for fifteen 
minutes, decant the supernatant liquid through a filter, agitate the remain- 
ing precipitate with 10 mils of diluted acetic acid, transfer the precipitate 
to the filter, and wash with 10 mils of diluted acetic acid. Return the 
filter and precipitate to the original flask, add 50 mils of N/10 iodin V. S. 
and 20 mils of a mixture of equal volumes of hydrochloric acid and water. 
Stopper the flask and agitate it vigorously for a few minutes, and then 
titrate the excess of iodin with N/10 sodium thiosulphate V. S. It shows 
not less than 55 per cent of CaS. 

Each mil of N/10 iodin V. S. used corresponds to .003607 gram of 
CaS. Each gram of crude calcium sulphide corresponds to not less than 
152.5 mils of N/10 iodin V.S. 

SULPHUR OXYACIDS 

The sodium and some of the potassium salts of the sulphur oxyacids 
are used quite extensively in medicine. Sulphate of magnesium is a well- 



956 INORGANIC SECTION 

known household remedy. Certain proprietary sulphur remedies consist 
of mixtures of the alkali and alkaline earth salts of one or more of all of 
the sulphur acids and were formerly labeled " Soluble sulphur." To dis- 
tinguish the several combinations of sulphur acids a solution may be 
examined as follows: The sulphide is separated by agitating the solution 
with lead or cadmium carbonate and filtering. Barium chloride is then 
added to the filtrate and the sulphate and sulphite precipitated. After 
filtering, the filtrate is treated with hydrochloric acid and the thiosulphate 
will be decomposed with precipitation of sulphur and evolution of sulphur 
dioxide. The mixed sulphates and sulphite of barium are then treated 
with hydrochloric acid which will dissolve the sulphite, and on filtering 
and adding chlorin water to the filtrate the sulphurous acid will be 
oxidized to sulphuric acid with precipitation of barium sulphate. 

The sulphur as sulphate in an unmixed medicinal chemical is usually 
determined by the well-known procedure of precipitating with barium 
chloride in presence of hydrochloric acid, filtering onto a Gooch and weigh- 
ing or by ignition on a filter paper. 

Sodium sulphite is a salt which, on standing, will gradually oxidize to 
sulphate. The purity of a sample is determined by dissolving in recently 
boiled water and titrating with iodin in presence of hydrochloric acid. 
As a remedy it is employed as a germicide and anti-fermentative and 
should be looked for in tablets recommended for sour stomach and indiges- 
tion. Galenicals of this class often contain Nux Vomica and ipecac, and 
aqueous solutions prepared directly cannot be titrated with iodin. Sodium 
sulphite is sparingly soluble in alcohol and hence if its determination is 
desirable an aqueous solution of the tablet is filtered, oxidized by boiling 
with chlorin or bromin water, and the sulphate precipitated with barium. 
In case a water-soluble sulphate is simultaneously present, the filtered 
aqueous solution is made up to a definite volume, the sulphate determined 
in an aliquot and a second portion subjected to the chlorin oxidation. 

Thiosulphate of sodium is an antiseptic and germicide, and is employed 
in parasitic skin diseases, sore mouth, diphtheria, diarrhea, typhoid fever, 
dyspepsia, etc. The purity of a sample is determined by titration with 
iodin in neutral solution. 2Na 2 S203+l2 = 2NaI+Na2S406. If this salt 
occurs in admixture and titration is not feasible, it may be converted into 
the sulphate by means of chlorin or bromin water and then determined. 

PHOSPHORUS AND ITS ACIDS 

Phosphorus, as an element, is a component of a class of medicines 
known as lost-manhood restorers, and will be found in pills, tablets and 
elixirs alone and combined with Nux Vomica, damiana, cantharides, coca 
cinchona alkaloids, iron salts, aloes, Digitalis, belladonna, Cannabis sativa, 



NON-METALS AND THEIR COMPOUNDS 957 

zinc, and other valerianates, opium alkaloids, ipecac, and metallic phos- 
phides. It is also combined with cod-liver oil in capsules. The analyst 
who undertakes the examination of galenical preparations will often meet 
with phosphorus in combination with one or more of these drugs. This 
element is also found to a considerable extent in rat poisons, and its detec- 
tion is of considerable importance in toxicological investigations. 

Phosphorus used in medicine is the yellowish stick form. Its detection 
is simple, especially when it occurs in elixirs, for it distills when the mix- 
ture is boiled, and in making an alcohol determination it will be found in 
the distillate. It is good practice, after determining the specific gravity 
of the distillate, to add a slight excess of chlorin water and allow the solu- 
tion to stand an hour or more. If phosphorus is present it is oxidized 
to phosphoric acid, and on boiling off the excess of chlorin and adding 
ammonium molybdate a yellow precipitate will appear. 

If phosphorus is suspected in pills or tablets it can be dissolved by 
triturating the ground material with alcohol. The alcoholic solution is 
filtered, diluted with water, and subjected to distillation, whereupon the 
phosphorus will appear in the distillate. In the general scheme of qualita- 
tive analysis a small portion of the alcoholic extraction should be reserved 
for the above test. 

Ewe and Vanderkleed 1 have described a simple method for determin- 
ing free phosphorus in rat pastes, which is applicable to tablet and other 
preparations containing the substance in the elemental state. The sample 
amounting to about a gram in the case of a rat paste, and considerably 
more of a galenical is placed in a distilling flask connected with a carbon 
dioxide generator and a condenser, the condenser being connected with 
a 300-mil Erlenmeyer flask containing 50 mils of 3 per cent silver nitrate 
solution. The Erlenmeyer flask is connected in series with two U tubes 
containing 3 per cent silver nitrate solution. All connections exposed to 
the phosphorus should be of glass or cork covered with plaster of paris. 
A stream of carbon dioxide is passed through the apparatus for twenty 
minutes and the joints examined for leaks with flexible collodion; 125 mils 
of cold, freshly boiled distilled water containing 2 mils of sulphuric acid 
are introduced into the flask containing the sample by means of the tube 
which leads to the carbon dioxide generator. The current of gas is con- 
tinued, and the flask gently heated until, after about three hours, prac- 
tically all of the liquid has been distilled into the silver nitrate solution. 
The condenser is allowed to become hot from the distillation, and the 
generator is disconnected and the flame removed. All of the silver nitrate 
solution is then collected in the Erlenmeyer flask, using nitric acid to dis- 
solve any black precipitate in the U tubes. Fifteen mils of nitric acid are 
added to the mixture, boiled for five minutes and a slight excess of hydro- 
1 J. Amer. Pharm. Assn., 3, 1914, 1684. 



958 INORGANIC SECTION 

chloric acid to precipitate the silver. After boiling until the silver chloride 
separates out completely, the flask is cooled and the liquid filtered and 
concentrated to 150 mils. It is then cooled, excess of ammonia added, 
followed by nitric acid, the phosphate precipitated by molybdate, and the 
determination completed by the customary procedure. 

Estimation of Yellow Phosphorus. — Engelhardt and Winters 1 give the 
following method: The phosphorus, deprived of any oxidation products 
by scraping, is dried in an atmosphere of carbon dioxide, weighed, dis- 
solved in chloroform free from air, and made up to volume, the solution 
adjusted so that 10 mils corresponds to .03656 gram of phosphorus. Ten 
mils of the solution are received in a bottle with 15 mils 10 per cent copper 
nitrate from which the air had been expelled by heating; the air in the 
bottle replaced by carbon dioxide, and the mixture shaken for one-quarter 
hour. Hydrogen peroxide is added, the mixture shaken until the black 
color of the copper phosphide disappears, the aqueous solution separated, 
the chloroform washed twice with 15 mils water, the combined aqueous 
solution and wash-waters after the addition of nitric acid evaporated to 
5 mils testing from time to time for unoxidized phosphorous acid. When 
oxidation is complete the phosphoric acid is estimated in the aqueous 
liquid as mangnesium pyrophosphate. 

Phosphorus Resin. — Four grams of the resin (accurately weighed) are 
dissolved in 50 mils air-free chloroform in a separator, 20 mils air-free 
water added, the air in the separator replaced by carbon dioxide and the 
mixture shaken for one-quarter hour. An aliquot of the chloroform solu- 
tion is then drawn off and treated with copper nitrate as given above. 

Phosphorus Paste. — About 1 gram of the paste (accurately weighed) 
is mixed in a bottle filled with carbon dioxide, with 25 mils of air-free 
chloroform and 25 mils of air-free water, and the mixture shaken for 
fifteen ixrinutes. After separation the aqueous layer is siphoned off, and 
the chloroform shaken once more with 15 mils of air-free water to remove 
the last traces of oxidation products of the phosphorus. The water is 
again separated, the chloroform solution treated with copper nitrate solu- 
tion, and the estimation continued as above. 

Spirit of Phosphorus. — Twenty-five mils of spirit are mixed with 50 
mils air-free chloroform and 50 mils water, the mixture well shaken, and 
when complete separation has taken place the chloroformic solution drawn 
into a flask filled with carbon dioxide. The aqueous solution is shaken 
with two more portions of 25 mils each of chloroform, the combined chloro- 
formic liquids treated with copper nitrate in the usual way and the esti- 
mation completed as above. 

Phosphorus Pills. — A quantity of pills equivalent to about one grain 
of phosphorus is mixed in a bottle with 25 mils of air-free water and 100 
1 J. Am. Pharm. Assn., 1915, 4, 451. 



NON-METALS AND THEIR COMPOUNDS 959 

mils of air-free chloroform. The air in the bottle is replaced by carbon 
dioxide and the mixture well shaken until the pills are disintegrated. After 
allowing the liquids to separate as much as possible the aqueous layer is 
siphoned off. The mixture is then shaken with sufficient tragacanth to 
eliminate the remaining water, an aliquot of the chloroformic solution 
filtered off, treated with copper nitrate, etc. 

Elixir of Phosphorus. — Twenty-five mils of the elixir are mixed with 
50 mils air-free water in a separator, the air displaced by carbon dioxide, 
and the mixture shaken with 50, 25, and 25 mils air-free chloroform. The 
combined chloroformic liquids are shaken out once with 10 mils of air- 
free water to wash out any phosphorus oxidation products, separated and 
the chloroform solution treated with copper nitrate in the regular way. 

PHOSPHORUS COMPOUNDS 

The phosphorus compounds occurring in medicinal preparations con- 
sist of the salts of phosphoric, hypophosphorus and glycerophosphoric 
acids, phosphides and organic substances containing phosphorus in com- 
bination. Plant extracts contain phosphates and probably organic sub- 
stances containing phosphorus. The coatings and subcoatings of pills and 
tablets sometimes contain phosphates, so that the presence of phosphates 
does not necessarily indicate that it is there as a remedial agent. 

Of the phosphides, the zinc compound is the only one of importance, 
and it may occur in the same class of mixtures that elemental phosphorus 
does and the remedies are used for the same purpose. 

Sodium phosphate is an important drug. Calcium phosphate is used 
as a remedy and is an important constituent of dentifrices. It is also 
employed as a mechanical agent in molding pills and tablets. 

Iron phosphate and pyrophosphate are important and potassium phos- 
phate is used as an alterative. Magnesium phosphate is of lesser impor- 
tance, as are the lactophosphates of the alkalies and alkaline earths, which 
are probably mixtures of the salts of the two acids, lactic and phosphoric. 
The glycerophosphates have been treated under ethereal salts. 

The hypophosphites of the alkalies, certain of the alkaline earths, and 
iron and manganese are important medicinal agents and are to be found 
largely in reconstructive tonics. The phosphites are of no importance 
in this work. 

The most delicate reaction of the phosphates is the production of the 
canary-yellow precipitate, when a solution of the substance in the pres- 
ence of nitric acid is warmed with an excess of ammonium molybdate. 
Silver nitrate gives a yellow precipitate with soluble orthophosphates and 
white precipitate with pyrophosphates and metaphosphates. 

Magnesium sulphate gives a white precipitate with pyrophosphates, 



960 INORGANIC SECTION 

soluble in excess of magnesium sulphate and not reprecipitated in the 
cold by ammonia. It does not precipitate metaphosphates in the pres- 
ence of ammonium chloride. 

Egg albumen is coagulated when shaken with metaphosphoric acid 
or with metaphosphates acidified with acetic acid. The ortho and meta 
acids are without action. 

Phosphites are strong reducing agents. With silver nitrate a precipi- 
tate is produced which is momentarily white but which soon blackens. 
Mercuric salts are reduced to mercurous, and then to metallic mercury. 
When strongly heated, phosphites decompose, giving off phosphoretted 
hydrogen. 

Hypophosphites are all soluble in water. They are even more power- 
ful in their reducing action than phosphites. On adding copper sulphate 
to an acidulated solution of a hypophosphite and gently warming, a yellow- 
ish-brown precipitate is formed which quickly changes to chocolate-brown. 
This reaction distinguishes the hypophosphites from phosphites. When 
gently heated, hypophosphites evolve phosphoretted hydrogen. 

The determination of the phosphoric acid radicle in soluble phosphates 
may be accomplished by the well-known method of precipitation with 
ammonium molybdate in presence of nitric acid and either titrating the 
precipitate or converting it to magnesium pyrophosphate. 

If organic substances are present, the precipitation with molybdate 
is not complete. When this situation arises the sample should be diluted, 
made strongly ammoniacal and precipitated with magnesia mixture. The 
precipitate is recovered and washed free from mother liquor, dissolved 
in dilute nitric acid, and subjected to the molybdate precipitation. In 
some cases it may be desirable first to boil the sample with concentrated 
nitric acid, then dilute, precipitate with magnesia mixture, and proceed 
as above. 

If the qualitative examination shows the presence of a pyrophosphate 
and it is desired to estimate the amount, the sample must be boiled with 
nitric acid before precipitating with molybdate. Mixtures containing 
pyrophosphates may contain organic matter, and after boiling with nitric 
acid, the solution should be treated with excess of ammonia, magnesia 
mixture added, and the well-washed precipitate dissolved in nitric acid 
and precipitated with molybdate. 

In some instances the addition of ammonia to a complex mixture will 
cause a precipitate to appear before the magnesia mixture is introduced. 
But the subsequent solution of the precipitate in acid and precipitation 
with molybdate will eliminate any foreign substances. 

Hypophosphites are readily determined by conversion to phosphates 
by oxidizing with nitric acid or permanganate. If by any chance soluble 
phosphates and hypophosphites occur together, the phosphate may be sep- 



NON-METALS AND THEIR COMPOUNDS 961 

arated by throwing it out of ammoniacal solution with magnesia 
mixture. 

Hypophosphites may be estimated by titration with permanganate. 
A dilute solution of the salt, free from organic matter, is acidified with 
dilute sulphuric acid, a slight excess of the reagent added and heated to 
80 to 90° C, any red color remaining is removed by titration with oxalic 
acid. A further quantity of permanganate is then added and the same 
procedure repeated until the titration with oxalic acid shows that oxida- 
tion is complete. 

The determination of phosphoric acid in glycerophosphates is accom- 
plished by boiling under a reflux a solution of the sample with sulphuric 
acid and potassium bichromate for two hours. At the end of this period 
the hot mixture is diluted with water, the excess of bichromate reduced 
with sodium sulphite, and after the addition of sodium acetate, the phos- 
phate precipitated with molybdate in presence of nitric acid. This pro- 
cedure may be modified by neutralizing with ammonia after reducing 
the bichromate and making a preliminary precipitation with magnesia 
mixture, as was recommended in the assay of complex mixtures containing 
phosphates. 



CARBON AND CARBONIC ACID 

Wood charcoal is often present in remedies for certain forms of dys- 
pepsia. It is dispensed alone with sugar and methyl salicylate, and in 
combination with mercurous iodide, with bismuth subnitrate, with mag- 
nesium oxide, with Nux Vomica, and often pepsin, Capsicum, and ginger 
are included in the formula. 

The identification of carbon is a simple matter, because it is the only 
black substance which will withstand the action of chlorin even at high 
temperature. When burned in the presence of air or oxygen, the only 
product of combustion is carbon dioxide. 

Wood charcoal may be determined with sufficient accuracy by dis- 
solving out the other components of the tablet or lozenge with water, 
boiling the residual insoluble material with strong hydrochloric acid or 
chlorin water, diluting and filtering onto a Gooch. In case the insoluble 
mixture contains resistant siliceous matter, the carbon may be estimated 
by ignition in the organic combustion apparatus and the resulting carbon 
dioxide collected and weighed in the potash bulb. 

Sodium bicarbonate is used in combination with a large number of 
different drugs, and in granular effervescent preparations and artificial 
mineral water salts. The normal carbonates are ingredients of many 
preparations, and the basic or subcarbonates of a few metals, notably 



962 INORGANIC SECTION^ 

bismuth, are extensively employed. Lithium carbonate is used as a 
diuretic and antirheumatic. 

Carbon dioxide, when dissolved in water, forms carbonic acid, H2CO3. 
The acid is capable of dissolving the normal carbonates of the alkaline 
earths and magnesium forming acid carbonates or bicarbonates. All 
normal carbonates are insoluble in water, except those of the alkalies. 
The acid or bicarbonates are all soluble, but on boiling their solutions 
they are converted into normal salts, which (except in the case of the alkali 
carbonates) are precipitated. 

The normal carbonates of the alkalies are readily distinguished from 
the bicarbonates. A cold aqueous solution of the latter does not color 
phenolphthalein, but on warming, effervescence takes place, owing to the 
escape of carbon dioxide, and the solution acquires a deep-pink color. 

These two classes of salts may also be distinguished by the difference 
in their behavior toward certain metallic solutions. With magnesium 
sulphate or chloride, normal alkali carbonates give a white precipitate 
of a basic carbonate, 

5MgS0 4 +5Na 2 C0 3 = MgO •4MgC03+5Na 2 S0 4 +C02 

Sodium bicarbonate gives no precipitate with magnesium salts, the car- 
bon dioxide being in sufficient quantity to redissolve the magnesium car- 
bonate, forming magnesium bicarbonate. 

With mercuric chloride the normal carbonates give a reddish pre- 
cipitate of a basic oxide, while the bicarbonate gives no precipitate. 

When strongly heated the normal carbonates of the alkali metals (not 
ammonium) remain unchanged. Those of the alkaline earths and other 
metals are converted into oxides with evolution of carbon dioxide. 

The presence of a carbonate is determined by the evolution of carbon 
dioxide when the substance is treated with dilute hydrochloric acid, the 
gas being identified by its action on lime or barytes water. Sulphur 
dioxide which also produces a white precipitate with these reagents is 
distinguished by its characteristic odor, but if the two gases are liberated 
together both may be identified by passing the mixture first through a 
solution of potassium permanganate, which will absorb the sulphur dioxide, 
and then into lime water. If the passage of the gases through the per- 
manganate be continued for a few minutes the color of the solution is 
entirely destroyed, and the liquid may then be tested for sulphuric acid 
by barium chloride. 

The determination of the CO3 radicle is seldom a matter of moment 
except in the cases of the alkali salts. In most of the other cases, after 
establishing the identity of the salt, the analysis proceeds to a determi- 
nation of the metallic element, and from this datum the percentage of salt 
is calculated. A consideration of the procedures to be adopted when 



NON-METALS AND THEIR COMPOUNDS 



963 



working with ammonium carbonate and ferrous carbonate is discussed 
under the heading of these individual compounds. 

The purity of an alkaline carbonate is determined by dissolving a 
weighed amount of the same in water and titrating with standard acid. 
The following table gives size of sample and amount of acid required for 
neutralization if the assay is conducted according to the U. S. P. recom- 
mendations. 





Sample 


H 2 


Acid 


Alkali 


Ammonium Car- 








Not more than 


bonate 


2 grams 


50 mils 


50 mils N/1 H 2 S0 4 
boiled 


12.7 mils 
N/KOH, Indi- 
cator litmus. 


Lithium Car- 










bonate 


0.5 gram 




20 mils N/1 H 2 S0 4 


Not more than 

6.6 mils 

N/KOH. ln- 
. dicator methyl 

orange. 


Potassium Car- 










bonate dried 






Not less than 14.3 


Indicator methyl 


at 130° 


1 gram 


50 mils 


mils N/1 H 2 S0 4 


orange 


Sodium Carbon- 










ate 


1 gramNa 2 C0 3 -H 2 


10 mils 


Not less than 32.3 


Methyl orange 




.855 gram Na 2 C0 5 




mils N/1 H 2 S0 4 




Magnesium Car- 










bonate recent- 










ly ignited and 










cooled 


0.4 gram 




25 mils N/1 H 2 S0 4 


Not more than 
5.8 mils N/1 
KOH. Methyl 
orange. 



The total carbonate in a granular effervescent salt is determined by 
treating the sample with dilate sulphuric acid and aspirating the evolved 
CO2 into tared potash bulbs or tubes of soda lime. 

Tube E contains pumice moistened with sulphuric acid, tube D con- 
tains pumice impregnated with anhydrous copper sulphate (prepared by 
soaking in strong copper sulphate solution and drying at 200° C.) and serves 
the purpose of absorbing acid vapors, tube A is filled about four-fifths 
with soda lime the remaining portion a, furthest removed from the incom- 
ing gas, being filled with dry calcium chloride. F is a guard tube of soda 
lime, G is a tube containing sufficient concentrated sulphuric acid to cover 
the bend, S contains soda lime for removing CO2 from the air during 
aspiration. 



964 



INORGANIC SECTION 



The sample amounting to one to two grams is weighed into B, the 
stopper covering the funnel with 25-50 mils dilute sulphuric acid is inserted, 
and the apparatus connected, the absorption tubes A and F having been 
previously weighed. The acid is allowed to enter the flask slowly, the 
rate regulated by the escape of bubbles through tube G, which should not 
be faster than two per second. When effervescence is at an end the remain- 
der of the acid is admitted, the stopcock left open, tube S attached and 
a slow stream of air aspirated through the system, gentle heat being applied 
to B. The aspiration should be continued for twenty to thirty minutes. 




When the process is completed, the aspiration is stopped, the absorption 
tubes disconnected, the ends stoppered, cooled, and weighed. 

The same apparatus and procedure can be used for determining the 
carbonates of the heavier metals used for excipients, etc., in other classes 
of medicinal preparations. Hydrochloric acid should be substituted for 
sulphuric. 

SILICON AND SILICATES 



Insoluble silicates find their way into medicinal products chiefly as 
excipients. Their exact determination is seldom a matter of moment 
unless one is concerned with working out a formula to its ultimate compo- 



NON-METALS AND THEIR COMPOUNDS 965 

sition. In working with pills, tablets, and tooth powders it is usually 
sufficient to boil out everything that will dissolve in aqua regia, and then 
ignite the insoluble portion, and weigh the residue as siliceous matter. 

A complete analysis of an insoluble silicate is conducted as follows : 

From 1.5 to 3 grams of the silicate (which has been reduced to the finest 
possible powder, and dried) are weighed out into a platinum crucible of 
fairly large dimensions, and intimately mixed with five or six times its 
weight of fusion mixture, *(10Na2CO3 -I3K2CO3) by means of a stout 
platinum wire, or a thin glass rod with carefully rounded ends. The entire 
mixture should not more than hah fill the crucible. The covered crucible 
is then heated over a Bunsen flame, at first gently in order to expel the 
moisture present in the mixture, and afterward more strongly until the 
mass begins to melt round the edges. It is then heated by means of a 
blowpipe, until the decomposition is complete and the contents of the 
crucible are in a state of quiet fusion. Care must be taken, by regulating 
the heat of the blowpipe, to prevent undue frothing of the mass while 
the carbon dioxide is being evolved; the progress of the operation should 
be watched by momentarily slightly raising the crucible lid from time to 
time. 

When the operation is complete, the crucible is allowed to cool down, 
and when cold it is placed upon its side in a beaker with about 100 mils 
of water, care being taken that no impurities are conveyed into the solu- 
tion upon the outside of the crucible. The beaker is heated upon an iron 
plate or sand-bath, and the water allowed to boil gently until the " melt " 
is either entirely detached from the crucible or has become honeycombed 
by the action of the hot water. Hydrochloric acid is then cautiously 
added in small portions at a time (the clock-glass cover being partially 
withdrawn for each addition) until effervescence ceases, and no further 
precipitaion of gelatinous silicic acid takes place. The crucible and fid 
are then withdrawn and rinsed into the beaker. 

The mixture is transferred to a dish, and evaporated to dryness upon 
a steam-bath, the gelatinous mass, as it stiffens, being stirred at frequent 
intervals with a short glass rod, in order to break it up as much as possible 
and thus expedite the drying. When the mass has become white and 
pulverulent, the dish is transferred to an air-bath, and heated to about 
160° for hah an hour. 

The residue is then moistened with a little strong hydrochloric acid, 
and digested upon the steam-bath for a short time, acid being added as 
evaporation goes on. Hot water is added, and the silica washed several 
times by decantation with hot water, after which it is transferred to the 
filter and washed until the wash-water is free from chlorides. 

The silica is dried in the steam-oven, transferred to a platinum cru- 
cible, and the paper incinerated upon a platinum spiral. The covered 



966 INORGANIC SECTION 

crucible is heated, at first very cautiously with a small flame, and after- 
ward to a red heat, and weighed until constant. 

Aluminum silicate forms the base of a class of soothing antiphlogistine 
preparations popular as applications for wounds, and swellings and as 
substitutes for poultices. These products are usually sold under fanciful 
names suggestive of their antiphlogistic properties and consist of the base 
with glycerin, boric acid, menthol, thymol, eucalyptol and ammonium 
iodide. Cataplasm of kaolin of the U. S. P. is a type of this class of prod- 
ucts and contains 57,7 per cent kaolin, 

BORON AND BORATES 

Boric acid and sodium tetraborate are important medicinal agents. 
The latter is found in antiseptic dusting powders, gauzes, and washes; 
in soothing emollient preparations with glycerin, extract of witch hazel 
and Irish moss, as an excipient or lubricant in pills and tablets, and as 
an active ingredient of certain formulas used in cystitis, leucorrhea, and 
for gargles. It is found in eye washes, in liquids of the listerine type, 
and in ointments and salves combined with menthol, thymol, camphor, etc. 

Sodium tetraborate or borax is a constituent of many alkaline anti- 
septic tablets, washes, and gargles; it is combined with potassium chlorate, 
cocain hydrochloride, resorcin, etc., and will be found in cystitis mixtures. 
It has been used as a remedy for epilepsy. 

Sodium perborate, NaB03+4H20, is an antiseptic, deodorant, and 
bactericide, and liberates active oxygen when treated with dilute acids 
or water. It is used in the treatment of wounds, sores, ulcers, and dis- 
agreeable discharges, and is a component of certain classes of dentifrices, 
and so-called " peroxide " cold creams. 

Zinc borate and perborate are used in dusting powders for wounds 
and eczema, as are also calcium borate and magnesium borate, the latter 
known as " Antifugin." 

Boric acid is an ingredient of the antiphlogistic pastes popularly sold 
as applications for wounds and bruises following the formula of cataplasm 
of kaolin of the U. S. P. 

Determination of Boric Acid. — Boric Acid alone and in Talcum Powders 
Free from Carbonates. — The sample is treated with water, an equal volume 
of glycerin added and titrated with sodium hydroxide using phenol- 
phthalein. 

In the U. S. P. assay for boric acid, if 1 gram is dissolved in 50 mils 
of water, 50 mils of glycerin added, not less than 16.2 mils N/l sodium 
hydroxide should be required for neutralization. 

Boric Acid or Borates in Presence of Carbonates. — The sample is treated 
with standard acid until the solution reacts acid to methyl orange. It 



NON-METALS AND THEIR COMPOUNDS 967 

is then boiled under a reflux until carbon dioxide is expelled, cooled, neu- 
tralized to methyl orange, an equal volume of neutral glycerin added, and 
titrated with standard alkali using phenolphthalein. 

Borates insoluble in water are dissolved in dilute hydrochloric acid 
in the cold or under a reflux, and treated as above. 

Boric Acid and Borates in the Presence of Aluminum and Iron. — 
The sample is dissolved in hydrochloric acid and heated under a reflux 
until carbon dioxide is expelled. The mixture is cooled and made up to 
volume, an aliquot filtered off, nearly neutralized to methyl orange, barium 
carbonate added, warmed on steam-bath for half an hour, cooled, filtered, 
the filtrate treated with an equal volume of glycerin, and titrated as above. 

Boric Acid and Borates in Salves and Ointments. — Five grams of the 
sample are treated with 30 mils of neutral glycerin and 50 mils of water 
and warmed on the steam-bath until the ointment is melted. The aqueous 
liquid is then treated as usual. 

Another procedure is to dissolve the fats and oils in petroleum ether 
and wash the mixture with water. After separating, the ethereal layer 
is washed again with water and the combined aqueous solutions titrated. 

Separation of Boric Acid from Other Substances, as Methyl Borate. — 
The following procedure is described by M. F. Schaak: 1 

The apparatus for distillation may conveniently be arranged as follows: 
A long wide-necked 200-mil Kjeldahl flask may serve as the decomposing 
flask. This flask is fitted with a stopper carrying three tubes, one of which 
serves to connect it with a condenser in such a manner as to avoid any 
of the acid liquid being carried over during the distillation. Another tube 
is to be connected with a flask for supplying a current of methyl alcohol 
vapor which is to be conducted to the bottom of the decomposing flask, 
thus serving to keep the mixture agitated and avoid bumping during the 
distillation. The third tube serves to introduce the methyl alcohol needed 
to form the mixture with the sulphuric acid and the substance, and may 
also be fitted with a clamp and valve for equalizing the pressure when 
needed. The receiver which is a tube connected with the condenser is 
trapped with a Mohr's bulb. 

For the estimation a portion of the dry, finely pulverized substance 
is placed into a long, narrow tube and weighed. The contents are then 
emptied into the decomposing flask, without allowing any of the sub- 
stance to remain in the neck of the flask. The tube is now weighed again, 
the difference being the amount of substance used for the estimation. 

A sufficient amount of concentrated sulphuric acid is added to form a 
thin paste with the substance, and the flask heated gently to expel carbon 
dioxide or other volatile acid, and cooled. 

About 60 mils of water are placed in the receiver, the terminal tube 
1 J. Soc. Chem. IncL 1904, 23, 700. 



968 INORGANIC SECTION 

of the condenser being made to dip into the water. The Mohr's bulb is 
also filled with water and attached as a trap to the receiver. The decom- 
posing flask, containing the cold mixture of the substance and sulphuric 
acid, is now connected with the flask for the generation of methyl alcohol 
vapor, and with the condenser, all the connections being air-tight. 

The distillation is then started by adding to the decomposing flask, 
in one portion, sufficient cold methyl alcohol to equal about 20 times the 
amount of free sulphuric acid present. Methyl alcohol vapors are then 
passed from the generating flask until the boric acid has all passed into 
the receiver. 

During the distillation the decomposing flask is heated to a temper- 
ature sufficient to prevent any marked change of volume of the methyl 
alcohol which was originally added. 

The distillation will usually be complete in about thirty minutes, when 
the receiver can be changed, and, to ensure complete removal of the boric 
acid from the substance, a further distillate collected and tested. 

The water from the Mohr's bulb is added to the distillate, which is 
then neutralized with alkali, when necessary, by the aid of Congo-red 
or methyl orange test-paper. The titration is then completed after the 
addition of neutral glycerol and phenolphthalein. 

When pure methyl alcohol is used and care is taken not to allow the 
mixture with sulphuric acid in the decomposing flask to become concen- 
trated, accurate results can be attained, even in the presence of large 
amounts of chlorides and carbonates. Fluorine, when present in large 
amount, must be removed from the substance before distillation. 

PERBORATES 

The perborates have assumed considerable prominence during recent 
years because of the ease and rapidity by which hydrogen peroxide is 
evolved when they are treated with water or dilute acids. Certain salts 
of other acids containing a large amount of oxygen have been placed on 
the market and the analyst will be confronted with the problem of decid- 
ing which particular substance has been used in compounding a mixture. 
Lenz and Richter : have studied the reactions of a number of these sub- 
stances toward certain reagents. They compare the behavior of (a) 
sodium perborate, (b) potassium percarbonate, (c) ammonium persulphate, 
(d) potassium perchlorate, and (e) periodic acid; a and b are decomposed 
by water with the formation of hydrogen peroxide and liberation of 
oxygen; c gives oxygen only. Permanganate solution in the presence 
of sulphuric acid is decolorized by a and b and by c slightly on heating; 
d and e have no effect; alkaline permanganate is turned blue by d. With 
1 Znal. Chem., 1911, 50, 537. 






NON-METALS AND THEIR COMPOUNDS 969 

silver nitrate solution a heavy black precipitate is produced by a (a mirror 
on warming in the presence of ammonia) ; a white precipitate turning gray 
on warming, with b; a solution of c becomes turbid through the separation 
of blue molecular silver; d has no action; e gives a pale-yellow precipitate 
readily soluble in ammonia, a, b, c, and e cause the darkening of freshly 
precipitated manganous hydroxide (in absence of air); d has no effect. 
The precipitate obtained by adding sodium hydroxide to cobalt nitrate, 
in absence of air (under petroleum ether) is darkened at once by a, b, and 
c, but not by d and e. When nickel sulphate is treated similarly, a black 
precipitate is given by c; the others have no effect. Alkaline lead acetate 
solution, when heated with an excess of c, gives a yellow-red precipitate 
after a time; with e a heavy white crystalline precipitate is obtained; a, 
b, and d have no effect. Cerous chloride solution, in the presence of 
ammonia, is colored yellow by a and b; the others have no effect. Iodin 
is liberated from potassium iodide by c, and in the presence of sulphuric 
acid by a and b; d has no effect. Fuchsin solution, containing sodium 
acetate, is decolorized by a, b, and c on warming, but not by d. Anilin 
sulphate solution is colored a pale yellow when heated with a or b ; c gives 
a dark-brown precipitate and d has no action. 

E. K. Farrar l has proposed the following method for the estimation 
of perborates. A known weight of the sample in the solid condition is 
added to an excess of ferrous ammonium sulphate in water which has been 
acidulated with sulphuric acid. Potassium thiocyanate is added as an 
indicator, and the ferric iron titrated with a standard solution of titanous 
chloride. An alternative method consists in adding the sample to a 
measured volume of titanous chloride solution which must be in excess 
(the operation being performed in an atmosphere of CO2) and titrating the 
excess of titanous chloride with iron alum, using potassium thiocyanate 
as indicator. 

Estimation of Perborates in Soap Mixtures, Creams, etc. — The sample 
is weighed into a glass-stoppered volumetric flask, water added, warmed 
to 50 to 60° and shaken for five minutes. Dilute sulphuric acid is added 
in excess, followed by 1 gram ignited kieselguhr, the solution made up to 
volume and allowed to settle. Aliquot s are then filtered off and titrated 
with permanganate. 

1 J. Soc. Dyers and Col., 1910, 26, 81. 



CHAPTER XXVI 
METALS AND THEIR COMPOUNDS 

SILVER 

Silver compounds are important therapeutic agents. They function- 
ate as antiseptics and bactericides, and in some forms are introduced 
directly into the blood stream. Silver salts are also employed as alter- 
atives, stimulants, and nerve sedatives, and preparations containing them 
will be found recommended for a wide range of ailments, including epilepsy, 
locomotor ataxia, typhoid fever, chronic diarrhea, gastric troubles, etc. 
They find their widest use in gynecological practice, and on account of the 
demand for non-irritant agents, there have sprung up a quantity of organic 
silver compounds of indefinite composition. Of late silver salts have been 
exploited as cures for the tobacco habit. 

The salts used as medicaments include the nitrate, acetate, arsenite, 
chloride, citrate, cyanide, iodate, iodide, lactate, and sulphocarbolate. 
The oxide, mixed with chalk, is dispensed in capsules. The organic com- 
binations are chiefly of a proteid nature, and will be discussed individually. 

Silver nitrate is recognized in the U. S. P. Molded silver nitrate or 
lunar caustic is the crystalline salt with 4' per cent hydrochloric acid. 
Mitigated silver nitrate U. S. P. contains 33J per cent of the crystalline 
salt, with the balance potassium nitrate. It is sometimes called mitigated 
lunar caustic No. 4. Two other mixtures of these two salts are marketed, 
one containing 67 per cent and the other 50 per cent AgN03, and known 
respectively as mitigated lunar caustic No. 2 and No. 3. These remedies 
are used in the treatment of the diseases above mentioned, and are locally 
applied hi gonorrhea, conjunctivitis, cystitis, stricture, excrescences, warts, 
ulcers, hemorrhoids, chancre, diphtheria, hydrocele, smallpox, etc. 

Silver cyanide and oxide are both recognized in the U. S. P. Silver 
in inorganic combinations is readily recognized when conducting the regular 
scheme of qualitative analysis, but when in organic combinations and 
under certain conditions in the presence of organic acids, it does not respond 
to the analytical reagents. When the latter condition prevails the organic 
matter must be destroyed by digestion with nitric and sulphuric acid before 
the identification tests can be applied. 

For assaying silver nitrate crystals, molded silver nitrate and mitigated 

970 



METALS AND THEIR COMPOUNDS 



971 



silver nitrate, the pharmacopoeial procedure consists in dissolving the salt 
in 10 mils of water, adding a certain quantity of sodium chloride standard 
solution and then titrating back with a certain limited amount of silver 
nitrate. 



Amt. used 



N/10 NaCl 



N/lOAgNOa 



Indicator 



Silver Nitrate. . 

Molded silver nitrate .... 
Mitigated silver nitrate. . 



0.5 gram 
0.5 gram 
1 . gram 



30 mils 
30 mils 
20mi]s 



0.4 mil 
1.9 mils 
0.3 mil 



3 drops K 2 Cr0 4 
3 drops K 2 Cr0 4 
3 drops K 2 Cr0 4 



In assaying silver cyanide, the salt is fused in a porcelain crucible, and 
after ignition, should leave a residue of metallic silver amounting to 80.48 
per cent of its original weight. 

No better method for estimating silver exists than precipitating a 
solution of the salt with dilute hydrochloric acid in presence of nitric acid, 
and weighing the silver chloride on a Gooch. 

If the sample in hand consists entirely of inorganic material, and the 
silver salt is soluble in water, and there are no other metals present pre- 
cipitated by hydrochloric acid, a weighed amount is diluted with water to 
about 100 to 200 mils, filtered if necessary from any insoluble residue, 
5 to 10 mils dilute nitric acid added, heated to boiling, and dilute hydro- 
chloric added until the precipitate coagulates and settles out, leaving the 
supernatant liquid clear when the flame is withdrawn. If the addition 
of a few drops of hydrochloric acid shows that the precipitation is complete, 
the silver chloride is collected on a tared Gooch, washed with water, rinsed 
with alcohol and ether, and dried at 100°. 

AgCl : Ag=l : 0-75202 

If the sample contains a halogen salt of silver, the metal may be 
obtained in a solution by fusing in a porcelain crucible, adding water, 
followed by a piece of pure zinc and some dilute sulphuric acid. The 
reduced spongy silver is afterward washed with dilute sulphuric acid and 
water, and then dissolved in nitric acid. 

If the sample consists of a colloidal suspension of silver oxide or an 
organic mixture, a weighed quantity is either evaporated or treated with 
10 to 15 mils concentrated sulphuric acid in a porcelain evaporating dish, 
and heated until well charred. After cooling, nitric acid is added, heated, 
and if the liquid does not char again after the nitrous fumes have all boiled 
away, it is cooled, diluted with water, and precipitated with hydrochloric 
acid, as above. Should lead or mercuric mercury be present simultane- 
ously with silver a small quantity of sodium acetate should be added to 
insure the complete precipitation of the silver chloride. 



972 INORGANIC SECTION 

In some cases it will be sufficient to ignite the substance in a porcelain 
crucible and weigh the resulting silver. Igniting should be gentle at first 
afterward with the full flame. If the substance leaves a residue which 
appears to contain silver chloride or a halogen salt, it is converted to me- 
tallic silver with zinc and sulphuric acid, and the determination completed 
by dissolving in nitric acid and precipitating with hydrochloric acid. 

COLLOIDAL SILVER 

Under certain conditions silver in a very fine state of subdivision forms 
a colloidal suspension which gives with water a mixture closely resembling 
a solution. Colloidal silver is not precipitated by the ordinary reagents 
which precipitate the metal from solution, thus sodium chloride or albu- 
men are without effect, but if the suspension is first warmed with nitric 
acid until the silver is dissolved, the resulting solution will respond to the 
usual silver tests. Colloidal silver is used for the preparation of ointments, 
dusting powders, vaginal tampons, suppositories, and tablets. 

Among the colloidal preparations on the market may be mentioned, 
Cargentos, Collargol, and Electrargol. 

Cargentos is said to be prepared by precipitating an alkaline solution 
of silver casemate and silver oxide with an acid, chssolving the precipitate 
in an alkali, dialyzing the resulting solution against running water and 
evaporating the remaining colloidal suspension to dryness in vacuo. It 
occurs in odorless and tasteless black scales of metallic luster, which fonxi 
colloidal suspensions with water and glycerin. It contains from 48 to 52 
per cent metallic silver. 

Collargol occurs in hard, brittle, bluish-black, scale-like pieces, forming 
with water a dark olive-brown colloidal suspension. 

Electrargol is a colloidal suspension of silver containing a small per- 
centage of sodium arabate. It contains silver equivalent to .25 per cent. 
It is prepared by passing an electric current in the form of an arc between 
two silver electrodes in distilled water. It is made stable by the addition 
of sodium arabate. The liquid is odorless and tasteless, appearing trans- 
parent by transmitted light and opaque and gray by reflected light. 

SILVER COMPOUNDS WITH PROTEIN SUBSTANCES 
Albargin. — Gelatosesilver 

Albargin is a compound of silver nitrate with gelatose, containing from 
13 to 15 per cent of silver. 

It is prepared by adding silver nitrate to a solution of gelatose in water, 
evaporating the solution or precipitating the compound by the addition 
of ether or alcohol. It is a coarse, yellow, shining powder, very easily 



METALS AND THEIR COMPOUNDS 973 

soluble in water, forming neutral solutions. The presence of gelatose, 
silver, and a nitrate can be shown by appropriate tests. It is incompatible 
with tannin and chlorides. 

Argonin. — Caseinsilver — Silvercasein 

Argonin is a compound of silver and casein containing 4.28 per cent 
of silver. 

It is prepared by precipitating an alkaline solution of casein with silver 
nitrate and alcohol. It is a fine, nearly white powder, easily soluble in 
water, forming an opalescent, faintly alkaline solution, which becomes 
clear on the addition of sodium chloride. It is also soluble in alkaline 
solutions, in egg albumen, blood serum, etc. 

The usual reagents for silver do not affect its aqueous solution (1 in 
20), which should remain clear on addition of sodium chloride, and should 
not be affected by hydrogen sulphide. On incineration argonin should 
yield at least 4 per cent of silver, which may be identified by the usual 
tests after solution in dilute nitric acid, It is incompatible with acids. 

Argyrol. — Silver Vitellin 

Argyrol is a compound of a derived proteid and silver oxide, containing 
from 20 to 25 per cent of silver. 

The so-called vitellin is said to be prepared by electrolytic decompo- 
sition of serum albumin. To this product, finely suspended in water, is 
added freshly precipitated, moist silver oxide and the mixture is heated 
under pressure until combination occurs. The liquid is then evaporated 
to dryness in vacuo. The change in the proteid is in question; probably 
a compound of hydrolyzed proteid (serum albumin) and silver oxide is 
formed. 

Argyrol occurs in black, ghstening, hygroscopic scales. The solution 
is yellowish or black, depending on concentration, and is not affected by 
boiling. Solutions of argyrol stain the skin. It gives a slight cloudiness 
or precipitate with sodium chloride and hydrochloric acid; on addition 
of ferric chloride the color is discharged with formation of a white cloud. 
With alkali and copper sulphate it gives a slight biuret reaction. It has 
a slight metallic taste. Silver is recognized in the usual way. 

The compound is said to be incompatible with acids and most of the 
neutral and acid salts in strong solution. 

Hegonon. — Silver Nitrate Ammonia Albumose 

Hegonon is a substance obtained by treating silver ammonium nitrate 
with albumose, said to contain approximately 7 per cent of organically 
combined silver. 



974 INORGANIC SECTION 

It is a light-brown powder readily soluble in water. Its aqueous solu- 
tions do not coagulate albumin, even on heating, nor are they precipitated 
by sodium chloride. 

Novargan. — Silver Proteinate 

Novargan is an organic silver-albumin compound containing 10 per 
cent of silver. 

It is a fine yellow powder, soluble in water, forming a practically neutral 
solution, from which it is not precipitated by sodium chloride, nor affected 
by the usual reagents for silver salts. 

The solution is darkened by hydrogen sulphide or ammonium sulphide, 
but no precipitate is produced. 

Protargol. — Protein Silver Salt 

Protargol is a compound of albumin and silver, containing 8.3 per cent 
of silver in organic combination. 

According to the patent specifications insoluble protein silver com- 
pounds, obtained by treating protein bodies with silver salt, are rendered 
soluble by treatment with a solution of albumoses. 

It is a light-brown powder, soluble in twice its weight of cold water, 
producing a solution which is not affected by the ordinary precipitants 
of silver salts, such as alkalies, sulphides, chlorides, bromides, iodides, 
nor by heat. 

Ammonium sulphide gives a dark color to the solution without pre- 
cipitation. Addition of strong hydrochloric acid produces a precipitate 
of unchanged protargol, soluble in a large quantity of water. A solution 
containing sulphuric acid is not colored blue by diphenylamine. It is 
compatible with picric acid and picrates and with most metallic salts. 

Sophol 

Sophol is a compound of silver and methylene-nucleinic acid, contain- 
ing about 20 per cent metallic silver. It is prepared by corrosion of insolu- 
ble silver compounds of methylene-nucleinic acid into soluble silver com- 
pounds by treatment with neutral salts, such as sodium chloride. It is 
a yellowish powder, readily soluble in water, insoluble in alcohol or ether. 
The aqueous solution has a faint alkaline reaction and is not precipitated 
by dilute sodium hydroxide or by sodium chloride. When boiled with 
dilute alkali it assumes a black color and the odor of formaldehyde is appa- 
rent. An aqueous solution yields a yellowish precipitate on warming 
with nitric acid ; the precipitate is soluble in ammonia, the solution becom- 
ing orange. 






METALS AND THEIR COMPOUNDS 975 

Nargol 

Nargol is a compound of silver and nucleinic acid and contains about 
10 per cent of metallic silver. 

Largin 

Largin is a protein compound of silver containing 11 per cent of the 
metal. It is a gray powder, soluble in water and glycerin. 

Argentamin. — Ethylene-Diamine-Silver Nitrate 

Argentamin is an aqueous solution of silver nitrate and ethylene- 
diamine, corresponding to 10 per cent of silver nitrate. 

It is prepared by dissolving 10 parts each of silver nitrate and ethylene- 
diamine in 100 parts of water. It is a colorless, alkaline liquid, turning 
yellow on exposure to the light, but not precipitable by chlorides or 
albumin. 

LEAD 

Lead acetate is astringent and sedative and will be found in pills and 
tablets combined with opium and camphor, and in astringent washes with 
Hydrastis alkaloids, zinc salts, and morphin. It is a component of liquid 
hair dyes when it occurs with suspended sulphur. Its solution is also used 
as an astringent eye lotion and as an injection and wash for gonorrhea. 
The subacetate is employed in solution, the 25 per cent strength being 
known as Goulard's extract and the 1 per cent solution being official. It 
is employed externally for burns, bruises, sprains, blisters, inflamed con- 
ditions of the eyes, ivy poison, erysipelas, and as an injection for gonorrhea. 

Lead sub-carbonate, 2PbC03-Pb(OH)2, is used as a dusting powder 
for burns, and occurs in ointments for ulcers, carbuncles, and skin diseases. 
It will be found in cosmetics, powders and creams. 

Lead nitrate is employed in a limited way for the same purposes as 
the acetate. Lead monoxid, PbO, the yellow oxide or litharge, is one of 
the forms in which lead is exhibited in ointments. The sulphite is used 
as a local application for erysipelas, scabies, and various skin affections. 
The tannate is used for the same purposes. 

Lead oleate is the lead compound present in lead plasters. It is soluble 
in alcohol, ether, and oil of turpentine. This compound is the basis of 
certain types of proprietary ointments recommended for raw sores and 
infections, bites of animals, wounds, etc., where it is combined with Peru 
or Tolu balsams. 

Lead sulphocarbolate is a crystalline salt soluble in water and alcohol. 
The diiodophenolsulphonate is known as Sozoiodole-lead, and is slightly 
soluble in cold water, and dissolves readily in presence of acetic acid. 



976 INORGANIC SECTION 

The identification of lead when present in inorganic combinations and 
in most of the organic compounds, will result when the regular scheme 
of analysis is followed. If one is working with a plaster or a stiff ointment, 
lead oleate will dissolve in ether, and on shaking with dilute sulphuric 
acid, insoluble lead sulphate is formed, which can be filtered out from the 
acid solution and identified by appropriate means. 

Lead is determined by conversion to the sulphate or sulphide. It the 
sample contains lead acetate or nitrate in solution in water, or capable of 
solution in water free from organic matter a weighed amoimt is filtered 
from any insoluble matter, and treated with an excess of moderately dilute 
sulphuric acid and double the volume of ethyl alcohol. After standing a 
few hours, the precipitate is collected on a tared ignited Gooch, washed 
with water, and alcohol, dried and ignited. If the solution contains nitric 
acid or a nitrate, it is advisable to evaporate on the steam-bath after the 
addition of the sulphuric acid until all of the nitric acid is expelled. The 
residue is then diluted, alcohol added and the remainder of the determi- 
nation conducted as above described. 

If the sample is a powder and contains lead carbonate or oxide, the 
lead is brought into solution by treatment with nitric acid. Should calcium 
salts be present simultaneously with lead, the precipitation with sulphuric 
acid cannot be followed, and resort must be had to the sulphide determi- 
nation. 

Ointments containing inorganic lead salts are first treated with ether 
to dissolve the fatty base, and the insoluble lead salts brought into solu- 
tion with nitric acid. 

Lead plasters or ointments containing lead oleate may be dissolved in 
ether, transferred to a separatory funnel, and shaken with dilute sulphuric 
acid. The acid layer containing the lead sulphate is conducted into a 
flask, and the ethereal layer repeatedly shaken, if necessary, with the acid 
until no further precipitate takes place. The combined acid mixtures are 
then treated with twice the volume of alcohol and the remainder of the 
determination conducted as above. 

If the plaster or ointment contains no other inorganic salt, the follow- 
ing procedure may be used : 

Determination of Lead in Mixed Galenicals. — If it is desired to deter- 
mine the lead in the whole plaster including the gauze, weigh out a sample 
of about 5 to 10 grams and place it in a tared porcelain evaporating dish 
of about 100 mils. 

If it is desired to determine the lead as the medicament alone, the 
plaster must be weighed then treatea with ether in a porcelain dish large 
enough to hold the plaster spread cut and the ethereal extract should be 
carefully transferred to the tared evaporating dish in which the sub- 
sequent digestion is to be made, and the solvent evaporated on the steam- 



METALS AND THEIR COMPOUNDS 977 

bath. After three or four washings and gauze will be free from the lead salt 
and may be dried and weighed, the difference in the weighing represent- 
ing the medicament. 

Cover the material in the evaporating dish with 100 mils of concen- 
trated sulphuric acid and heat over the steam-bath. Watch carefully 
and remove from the bath if there is violent frothing. When the mixture 
is thoroughly charred transfer to an asbestos plate and heat gently for 
an hour or more until SO3 fumes cease to be evolved. Cool. Add 5 mils 
fuming nitric acid and allow to digest until violent reaction is over. Add 
5 mils concentrated sulphuric acid and heat gently as before and remove 
flame if reaction becomes violent. After the last fumes of SO3 have been 
driven off, place the evaporating dish over the free flame and heat at a low 
heat so that carbonaceous matter will ignite slowly. 

If there still remains any quantity of resistant carbonaceous material, 
allow the dish to cool, add 5 mils fuming nitric acid and allow to digest 
overnight. Evaporate off excess of acid on steam-bath, add 5 mils con- 
centrated sulphuric acid. Heat gently over asbestos plate as before and 
finally ignite at low redness. This last treatment with nitric acid and 
sulphuric acid will generally yield a white residue. Cool and weigh as 
lead sulphate. 

Note. — To obtain an even heat and prevent spurting when evapo- 
rated over asbestos plate, place a pipestem triangle on the asbestos and 
the evaporating dish on this. 

When soluble lead salts occur in pills or tablets with organic matter 
which will yield a precipitate with lead, the sample should be well ground, 
triturated with water, and the aqueous liquid filtered. The residue is 
then triturated with 5 per cent potassium hydroxide which is poured into 
the filter, the alkaline liquor collected, and added to the aqueous solution. 
The solution is then subjected to a stream of hydrogen sulphide, and when 
precipitation is complete, the sulphide is collected on a tared Gooch, well 
washed with hot water, dried with alcohol, washed with freshly distilled 
carbon bisulphide, again washed with alcohol, dried at 100° and 
weighed. 

If zinc or iron are known to be present, the combined sulphides are 
filtered, washed, and then treated with dilute hydrochloric acid before 
addition of alcohol and carbon bisulphide. 

Assay of Goulard's Extract U. S. P. — Transfer about 1.5 gram, accu- 
rately weighed, to a 200-mil measuring flask, dilute with 50 mils recently 
boiled distilled water, then add 50 mils N/10 oxalic acid, agitate the mix- 
ture thoroughly for five minutes, fill to the mark with distilled water, and 
filter rejecting the first 20 mils of the filtrate. Add 5 mils of sulphuric 
acid to 100 mils of the filtrate (representing one-half the amount of solu- 
tion originally taken), warm to about 70° and titrate with N/10 permanga- 



978 INORGANIC SECTION 

nate. It shows not less than 18 per cent of lead.- Each mil of N/10 
oxalic used corresponds to .010355 gram of lead. 

MERCURY 

Mercury, its salts and organic compounds are important remedial 
agents. 

Metallic mercury in confection of rose is known as Blue Mass, and is 
used as a cathartic and alterative. Mercury with chalk is used as an anti- 
emetic and alterative, especially adapted for children. Blue mass is dis- 
pensed in pills and tablets by itself and in combination with ipecac and 
opium ; with colocynth compound alone and combined with ipecac, Hyos- 
cyamus, aloes, or rhubarb; with colocynth compound, ipecac, strychnin, 
and belladonna; with Podophyllum resin; with Nux Vomica, Hyoscyamus, 
Capsicum and Podophyllum resin; with aloes, jalap, and tartar emetic; 
with ipecac and Gelsemium; with quinin and black pepper oleoresin; 
with rhubarb and sodium bicarbonate ; with aloes and Podophyllum resin ; 
with Digitalis and squills; with aloes, scammony, croton oil, myrrh, and 
oil of caraway; with strychnin, ipecac, Capsicum, and gentian; with 
quinin, Colchicum, Hyoscyamus, and opium. 

Mercury and chalk is dispensed alone in pills and tablet triturates. 
It is combined with gentian, ipecac, and opium; with gentian, Nux 
Vomica and reduced iron; with salol and bismuth subnitrate; with opium, 
camphor, bismuth subnitrate, kino and sodium bicarbonate. 

Mercurial ointment consists of mercury in a fine state of subdivision, 
in a medium of suet and lard. Oleate of mercury is added in small amount 
in the preparation of the U. S. P. product. This preparation is used exten- 
sively to destroy parasitic infections, as a resolvent in glandular swellings, 
venereal disease, for smallpox, erysipelas, and chilblains. Compound 
mercurial ointment contains in addition to the regular formula, camphor, 
olive oil, and beeswax. 

Oxides of Mercury 

Red mercuric oxide or red precipitate, is used externally for chancres, 
ulcers, ringworm, and inflamed conditions of the eyes. The yellow oxide 
is employed in syphilis and in acute and chronic derangements of the 
alimentary tract, in typhoid fever, phthisis, and functional disturbance 
of the liver. These substances are administered chiefly in the form of 
ointments. 

Black oxide of mercury is oxydimercurous ammonium nitrate, 
Hg20+NH 2 Hg 2 N03, and should not be confused with the true oxides of 
mercury. 



METALS AND THEIR COMPOUNDS 979 



Mercuric Salts 

Mercuric chloride is employed as an antiseptic and germicide, both 
in professional and household practice. It is also used in syphilis, and 
externally as a stimulant and escharotic. Mercuric chloride pills and 
tablets are prepared in several different strengths from 1/1000 to 1/8 grain. 
Antiseptic tablets are composed of mercuric chloride with either 
ammonium chloride, sodium chloride, or citric acid, often colored red or 
blue. Antisyphilitic pills contain mercuric chloride and potassium iodide, 
sometimes with the addition of opium. Mercuric chloride is also com- 
bined with morphin and copper arsenite ; with quinin, ferric chloride, and 
arsenic chloride; with potassium iodide, ferrous iodide, arsenic iodide, and 
Nux Vomica; with opium and guaiac. Mercuric chloride is used in the 
preparation of antiseptic bandages and surgical dressings. 

Mercuric bromide is combined with the bromides of gold and arsenic 
in remedies for neurasthenic and anemic conditions. 

Mercuric iodide, red iodide, is used in syphilis, rheumatic conditions 
due to venereal disorders and scrofula, and externally for lupus. Mer- 
curic iodide is dispensed in pills and tablets alone and in combination 
with arsenic and ferrous iodides; with aconite, belladonna, and bryonia 
for tonsillitis; with morphin, sodium salicylate, and methyl salicylate. 
It is also used in the preparation of surgical soaps. 

Mercuric cyanide is recommended in diphtheria, membranous croup, 
and syphilis. It is used in the form of a gargle and tampons. 

Mercuric nitrate is used internally for syphilis and scrofula, and exter- 
nally for removing freckles and absorbing boils. 

Mercuric acetate, arsenate, benzoate, cacodylate, gallate, iodate, oxy- 
cyanide, phosphate, basic salicylate, carbolate, basic sulphate, are all 
used medicinally in limited amount. 

Mercurous Salts 

Mercurous chloride or calomel combines the general properties of mer- 
curial salts with those of a purgative and anthelmintic. Calomel is pre- 
pared for administration in pills and tablets of different strengths. It 
is combined with sodium carbonate ; with ipecac ; with ipecac and opium ; 
with Podophyllum resin and sodium bicarbonate; with bismuth sub- 
nitrate; with Capsicum; with santonin; with ipecac and bismuth sub- 
nitrate; with sulphurated antimony and guaiac, and castor oil (Antimony 
comp. U. S. P. Plummer pills); with colocynth compound; with opium; 
with rhubarb, colocynth compound, and Hyoscyamus; with colocynth 
compound, jalap, gamboge, Hyoscyamus, and oil of peppermint; with 
colocynth compound, jalap, ginger, gamboge, and rhubarb; with colocynth 



980 INORGANIC SECTION 

compound, jalap, and gamboge (Cathartic Comp. U. S. P.); with aloes, 
rhubarb, and soap; with morphin, Capsicum, ipecac, and camphor; with 
Podophyllum resin, colocynth compound, belladonna, ipecac, Nux Vomica, 
and oil of anise; with aloes, jalap, gamboge, Veronica officinalis, Capsicum, 
Veratrum viride, and croton oil; with colocynth compound, Nux Vomica, 
aloes, Hyoscyamus, and ipecac; with colocynth compound, Colchicum, 
and Hyoscyamus; with Euonymus, ipecac, Podophyllum resin, and aloin; 
with zinc sulphocarbolate, salol, bismuth subnitrate and pancreatin; with 
atropin, morphin, and aconite; with quinin, ipecac, opium, aconite, aloin, 
and Capsicum. 

Mercurous iodide (yellow iodide) is an antisyphilitic. It is dispensed 
in pills and tablets alone and in combination with opium; with charcoal; 
with Conium, Lactucarium, and opium; with Podophyllum resin, aloin, 
Hyoscyamus, and Nux Vomica. 

Mercurous bromide is used as an alterative and antiseptic. 

Ammoniated mercury, HgNH2Cl, or white precipitate, is obtained by 
precipitating mercuric chloride with excess of ammonia. This salt is 
used externally in skin diseases, syphilitic sores and eruptions, and is 
often found in cosmetics. The term " white precipitate " (precipite blanc) 
is confusing, as it is used by the French as a term for designating calomel. 

Mercury oleate, prepared from mercuric oxide and oleic acid, is one 
of the forms in which mercury is administered internally. 

Mercuric succinimide is a salt of mercury and succinic acidimide. 
When suspended in ether and subjected to a stream of hydrogen sulphide, 
the mercury is precipitated as sulphide and the succinimide can be sub- 
sequently recovered from the ether. 

Afridol 

Afridol is sodium hydroxymercuric toluylate, C6H 3 (CH3)(COONa)HgOH 
2:3:1. It is an odorless, tasteless white powder, difficultly soluble 
in neutral or acid media, but soluble in ammoniacal solution contain- 
ing ammonium chloride. Filtered aqueous solutions of afridol remain 
unchanged on the addition of ammonium sulphide solution or albumin 
solutions. 

If afridol is boiled with hydrochloric acid, an odor of benzoic acid is 
produced and the cooled solution when saturated with hydrogen sulphide 
yields a black precipitate of mercuric sulphide. This product is marketed 
in the form of a 4 per cent soap. 

Mercurol. — Mercury Nucleinate 

Mercurol is an organic compound of mercury with nucleinic acid from 
yeast, containing 10 per cent of metallic mercury. It is prepared by adding 



METALS AND THEIR COMPOUNDS 981 

a solution of mercuric chloride to an alkaline solution of nuclein, contain- 
ing an excess of alkali, precipitating the resultant nucleinate of mercury 
by the addition of alcohol and a concentrated solution of a neutral salt 
(sodium chloride), separating the precipitate, washing and drying it. 

It is a brownish-white powder, soluble in water, especially in warm 
water, insoluble in alcohol. Its watery solution has a distinct metallic 
taste, a weak alkaline reaction, and is not precipitated by alkalies, by 
albuminous liquids, nor hydrogen sulphide. 

Mercurol does not coagulate albumin; it has marked bactericidal 
power and possesses the pharmacologic action of soluble mercury com- 
pounds. 

It is recommended as a local antiseptic application and as an anti- 
syphilitic remedy. 

Sublamine. — Mercuric Sulphate Ethylenediamine 

Sublamine, HgSC>4-2C2H4(NH2)2+2H20, is a compound of one mole- 
cule of mercuric sulphate with two molecules of ethylenediamine. It- 
forms white needles, readily soluble in water and in 10 parts of glycerin, 
sparingly soluble in alcohol. It has an alkaline reaction; it contains 
about 44 per cent of mercury. It does not precipitate albumin from its 
solutions. 

Sublamine is a disinfectant. It is used as a substitute for mercuric 
chloride for hand disinfection, as well as in dermatology, gynecology, 
ophthalmology, and otology. 

Electr-Hg. — Electromercurol 

Electr-Hg is a colloidal suspension of mercury equivalent to .1 per 
cent metallic mercury and containing a small percentage of sodium arabate. 

Electr-Hg is prepared by passing an electric current in the form of an 
arc between two mercuiy electrodes in distilled water. It is made stable 
by the addition of sodium arabate, which is prepared by acting on acacia 
(gum arabic) with hydrochloric acid, precipitating the resultant arabic 
acid with alcohol and neutralizing the arabic acid with sodium carbonate. 

Electr-Hg is an odorless, tasteless liquid, appearing transparent and 
brown in color by transmitted light and opaque and gray by reflected light. 
The addition of potassium cyanide solution or of strong nitric acid yields 
clear, colorless solutions. The nitric acid solution responds to tests for 
mercury. 

Electr-Hg is claimed to have an action similar to that of the soluble 
salts of mercury. Locally it is said to produce no pain when given by 
intramuscular injection, and to leave no induration. 



982 INORGANIC SECTION 

Hyrgol is a colloidal form of mercury. It is a nearly black, substance, 
soluble in water and used for syphilis in the form of ointments and plasters. 

Calomelol. — Colloidal Calomel 

Calomelol is a colloidal form of calomel, containing albuminoids. 

According to the patent, this drug is prepared by acting on a solution 
of sodium chloride in presence of a proteid with mercurous nitrate and 
precipitating the colloidal calomel by means of alcohol. The precipitate 
is washed with alcohol, redissolved in water with the aid of a little alkali, 
and from this solution the colloidal calomel is obtained either by evapora- 
tion or by precipitation with alcohol. 

It forms a white-gray, odorless and tasteless powder, containing 80 
per cent of mercurous chloride and 20 per cent of proteids. With water 
it forms an opalescent suspension insoluble in alcohol, ether, and benzene. 
It is precipitated from its aqueous suspension by acids, the precipitate 
being redissolved by alkalies. 

Determination of Mercury. — The determination of mercury is accom- 
plished by conversion to the sulphide and weighing, by depositing the 
metal electrolytically, or by iodin titration. 

In 1911 the Committee on Quantitative methods of the Pharmaceutical 
Section of the American Chemical Society suggested the following method 
for assaying mercury salts, which is applicable to all the mercury 
compounds of the Pharmacopoeia as well as to other simple salts of 
mercury. 

Mercurous Chloride, Bromide and Iodide and Mercuric Iodide. — Weigh 
out accurately about .2 gram of the sample, dissolve in 20 mils water 
with the aid of 1 gram potassium iodide. Add 10 mils of 10 per cent 
sodium hydroxide followed by 3 mils of 40 per cent formaldehyde diluted 
to 10 mils with water. Warm on the water-bath for ten minutes or until 
complete precipitation of the mercury takes place, swirling the container 
occasionally. Decant through a Gooch filter, and wash the precipitated 
mercury thoroughly with water. Dissolve off the filter with 2 c.c or more 
concentrated nitric acid, washing the filter carefully with water. 

From this point the process may be applied also to Mercuric Oxide, 
by solution in 2 c.c. concentrated nitric acid. 

Metallic Mercury, Mercury with Chalk and Mercuric Nitrate. — Evaporate 
the solution to dryness on water-bath and take up with 2 mils concentrated 
hydrochloric acid and water sufficient to make 50 mils of solution. 

From this point the process is applicable to Mercuric Chloride by 
solution as above. Precipitate the mercury from this solution in the cold 
by a slow stream of hydrogen sulphide, let settle and filter onto a tared 
Gooch. Wash thoroughly with water and three times with alcohol. 



METALS AND THEIR COMPOUNDS 983 

Wash with recently distilled carbon bisulphide to remove any adhering 
sulphur, then with alcohol and finally with ether. Dry at 100 to 110° 
and weigh. HgS X .8621 = Hg. 

When carefully conducted this method gives good results and it is 
applicable to almost any pill or tablet containing salts of mercury. 

B. L. Murray proposes the following electrolytic procedures for assay- 
ing mercury compounds. 

If the mercury preparations of the U. S. P. are first converted into 
mercuric nitrate they are then readily subjected to electrolysis to determine 
the per cent of mercury. This is practical with mercuiy oxide red, 
mercury oxide yellow, metallic mercury, and with mercury with chalk. 
Solution of mercuric nitrate U. S. P. may also be assayed for the mercury 
present after proper dilution to bring it to the usual concentration. The 
general statement of the method is to dissolve about 0.5 gram sample in 
about 1 mil of nitric acid (sp. gr. 1.20), dilute to about 20 mils and subject 
the solution to electrolysis. Use the mercury cathode and the rotating 
anode, the latter revolving about 700 to 800 times per minute. The voltage 
should be 10 to 12, the amperage 3, and fifteen minutes at room temperature 
will be found sufficient time for the electrolysis to become complete. The 
mercury cathode is then washed with water, alcohol, and ether in the 
usual way, any increase in weight being due to the metallic mercury from 
the weighed sample with which the analysis began. Three-quarters of an 
hour or one hour easily covers the entire analysis from beginning to end. 

For ammoniated mercury, mercury iodide red, mercury iodide ^yellow, 
and mercurous chloride, a different procedure is advisable. These salts 
are all dissolved in solution of sodium sulphide and from this the mercury 
is deposited. The samples, about 0.3 to 0.5 gram, are weighed directly 
into the tared mercury cathode dish. Ten mils of solution of sodium sulphide 
(sp. gr. 1.18) are added and a current of 0.5 to 0.75 ampere and 4 to 5 volts 
is passed for half an hour. Use the rotating anode running about 500 revo- 
lutions per minute. The mercury from the samples is deposited on that 
of the mercury cathode and all is washed and dried in the usual way with 
water, alcohol, and ether. If any amalgam of sodium and mercury forms 
during the electrolysis allow the wash water to stand on it until it is all 
decomposed. 

Mercuric chloride is best treated in a simpler manner. To determine 
the mercury quickly in this place a sample of about 0.3 gram in a weighed 
mercury cathode dish, dissolve in 20 mils of water, and, after adding a layer 
of about 10 mils of toluene to protect the apparatus from chlorine gas, pass 
a current of about 1 ampere and 10 to 11 volts for fifteen minutes. The 
speed of the rotating anode to be used in this case is about 500 revolu- 
tions per minute. At the end of fifteen minutes the liquids may as usual 
1 J. Ind. & Eng. Chem. 1910, 2, 481. 



984 INORGANIC SECTION 

be removed by decantation and the mercury cathode washed, dried and 
weighed. 

Electrolytic Determination of Mercury in Mercury Oleates, Murray. 1 — 
About .7 to .1 gram of the oleate is weighed directly into a mercury cathode 
cup (such as a small beaker capacity 50 to 75 mils) . To this sample there 
are added 15 to 20 mils of 10 per cent hydrochloric acid and 15 mils of 
toluene. The cathode cup with its contents is placed within a somewhat 
larger crystallizing dish or beaker which later can be filled with cold water 
to keep the temperature of the reaction down as desired. After attach- 
ing the anode and making the connections in the customary way, electrol- 
ysis of this non-uniform mixture is begun, gradually and slowly increasing 
the current up to 3 amperes, using about ten minutes to do it. The cur- 
rent (3 to 3.5 ampers at about 8 volts) is then maintained for about thirty 
minutes, the anode rotating at about 800 revolutions per minute. As 
the electrolysis continues, the contents of the cup become heated nearly 
to the boiling-point of some of the constituents, thus melting the mercury 
oleate. It is essential that the mercury oleate should melt. If the liquid 
in the cathode cup becomes too hot and appears to boil over, it should be 
cooled down by pouring water into the crystallizing dish or other surround- 
ing vessel, but it should not be cooled down below 60° C. When the 
mercury is all deposited the cathode cup is washed out by siphonation 
in the customary way with water, after which the metallic mercury is 
washed with alcohol, dried with ether, and finally weighed. 

Electrolytic Determination of Mercury in Mercury Salicylates, 
Murray. — Put about .3 gram into the mercury cathode dish and dissolve in 
10 mils of sodium sulphide solution (sp. gr. about 1.18). To this solution 
are added 20 mils of 10 per cent potassium hydroxide solution. The mix- 
ture is now electrolyzed using a current of 1 ampere at 7 volts until the 
mercury is completely deposited, usually one-half hour being required. 
The anode should rotate about 500 revolutions per minute. Aiter the 
deposition the electrolyte is decanted, the mercury is washed with water 
until free from alkalinity, then with alcohol, finally with ether, and then 
weighed. 

Assay of Mercuric Chloride (Antiseptic) Tablets. -R. M. Chapin's 2 
method for the analysis of tablets containing mercuric chloride and 
ammonium chloride. 

Weigh 5 tablets, dissolve in water, dilute to 100 mils and pass through 
a dry filter, discarding the first 20 mils of filtrate. From the remainder 
pipette 10 mils (equivalent to one-half tablet) into a glass-stoppered 250- 
mil Erlenmeyer flask, add 2| grams pure powdered potassium iodide, mix 
to entirely dissolve, and then wash down the sides of the flask with 20 mils 
of normal caustic alkali. Add exactly 3 mils of 37 per cent formaldehyde 

1 J. Ind. and Eng. Chem., 8, 1916, 257. 2 Amer. J. Pharm., 1914, 86, 1. 



METALS AND THEIR COMPOUNDS 985 

solution, mix thoroughly, and let stand for at least ten minutes, swirling 
the flask occasionally. Then wash down the sides of the flask with a mix- 
ture of 5 mils of 36 per cent acetic acid with 25 mils water; mix, and with- 
out delay run in from a burette 25 mils of N/10 iodin while constantly 
swirling the flask. Stopper the flask tightly, shake vigorously for three 
minutes, then after giving the contents a final swirling motion leave at 
rest for two minutes. If then no undissolved mercury can be detected 
at the bottom, the stopper is removed, rinsed, together with the neck of 
the flask, with a stream from a wash-bottle, and the excess iodin titrated 
with N/10 sodium thiosulphate, adding starch solution only when the 
iodin is nearly consumed. 

Standardize the iodin solution by running a blank assay on 10 mils 
distilled water. 

Subtract the volume of thiosulphate solution used in the assay from 
that used in the blank. The difference jnultiplied by the factor .0271 "^r 
strictly N/10 sodium thiosulphate will give the average weight of mercuric 
chloride per tablet. For a direct check upon the value of the sodium 
thiosulphate solution run an assay on 10 mils of a 2\ per cent solution of 
mercuric chloride of known purity. 

While mercuric chloride is the most important active ingredient of 
tablets made according to Wilson's formula, nevertheless ammonium chlo- 
ride is an essential part of the formula, added in order to render the tablets 
easily soluble and to inhibit the formation of insoluble, and hence inactive, 
compounds of mercury. An assay of such tablets ought therefore to 
include an estimation of ammonium chloride, especially when a simple 
and convenient method is available 

The method for ammonium chloride adopted is an adaptation of the 
process of Ronchese, which is based on the reaction between formaldehyde 
and a neutral ammonium salt, whereby methylenamin, (CH^N^ is 
formed, the acid originally contained in the ammonium salt being released 
and becoming titratable with standard caustic alkali and phenolphthalein. 

Titration by standard alkali and phenolphthalein cannot of course be 
conducted in presence of mercuric chloride. This difficulty, however, is 
easily overcome by throwing the mercury into a complex ion through the 
addition of potassium iodide. The method is as follows: Into each of two 
150-mil Erlenmeyer flasks pipette 5 mils (one-fourth tablet) of the tablet 
solution previously prepared for the estimation of mercuric chloride (5 
tablets per 100 mils) and add to each flask 2 mils of a 20 per cent solution 
of potassium iodide. 

Dilute one volume of 37 per cent formaldehyde solution with three 
volumes of water, measure 20 mils of the mixture into a small flask, add 
.5 mil of phenolphthalein indicator solution, neutralize with N/10 barium 
hydrate or caustic alkali, then flow the solution over the sides of one of 



INORGANIC SECTION 

the flasks (flask A) containing tablet solution, and mix well. To the other 
flask (flask B) containing tablet solution add about 65 mils water. 

Now add to the flask A 25 mils water and titrate with N/10 barium 
hydrate or N/10 caustic alkali free from carbon dioxide until, by using 
flask B as a standard for comparison, a color change is perceptible (titra- 
tion A). 

Add methyl red to flask B and titrate with either N/10 acid or alkali 
as needed (titration B) . 

To titration A add titration B if performed with acid, or subtract if 
performed with alkali. The resultant figure multiplied by the factor 
.0214 for strictly N/10 alkali will give the average weight of ammonium 
chloride per tablet. 

For a direct check upon the value of the N/10 alkali run an assay 
upon 5 mils of a 2J per cent solution of pure ammonium chloride. 

Solutions, reagents, and water used should be free from carbon dioxide. 
Ordinarily titration B is very small, sometimes zero, but usually calling 
for the addition of a few drops of N/10 acid. 

As respects the end-points with the indicators it is only possible to 
state that up to the present time no blue or green tablets tested by the 
originator presented the slightest difficulty. The characteristic colors of 
the indicators of course do not appear in the presence of other coloring 
matter, but the change of tint, if standards of comparison are used, is 
delicate and distinct. 

Method for Determination of Mercuric Iodide in Tablets, A. W. 
Bender. 1 — Powder a sufficient number of tablets to represent 1 to 2 grains 
of iodide. Place in a 180-mil Erlenmeyer flask and add 20 mils 1-1 hydro- 
chloric acid. Add about .5 gram potassium chlorate and stopper with 
glass tube reflux condenser. Digest on sand-bath until iodide is all dis- 
solved. Cool and dilute with water to about 100 mils, removing and wash- 
ing condenser. Blow out chlorin with a current of air. Filter and wash 
insoluble matter by decant at ion. Add excess of ammonia, and precipi- 
tate immediately in the cold with a slow stream of hydrogen sulphide. 
Let stand for a few hours and filter onto a weighed Gooch, washing with 
water, etc., and drying as described above in determining mercury as sul- 
phide. 

Grams of HgSX 30. 17 = grains Hgl 2 . HgXl.955 = HgI 2 

Mercurial Ointments 

About 2 grams of the ointment are warmed with petroleum ether and 
treated with 15 to 25 mils N/10 iodin. The mixture is heated until the 
mercury and mercuric oxide are dissolved, after which it is transferred 
1 J. Ind. and Eng. Chem., 1914, 6, 753. 



METALS AND THEIR COMPOUNDS 987 

to a separator, the iodin solution drawn off and the petroleum ether layer 
washed with water. The combined aqueous and iodin solutions are then 
treated with excess of potassium hydroxide, and the mercury precipitated 
by the addition of 3 mils formaldehyde 40 per cent and warming. The 
balance of the determination from this point follows either of the two 
outlines above described. 

Determination of Mercuric Iodide in Ointments. — Hallaway x recom- 
mends warming 2.5 grams with potassium iodide solution, and the melted 
ointment shaken until the red color disappears. After cooling, the liquid 
is filtered into a stoppered flask, and the treatment of the ointment base 
repeated twice. Twenty mils of potassium hydroxide are added, followed 
by 3 mils of formaldehyde, and the mixture warmed and whirled. After 
one-half hour 25 mils of 33 per cent acetic acid are added, followed by 
25 mils N/10 iodin, the mixture shaken until the mercury is dissolved, 
and the excess of iodin titrated as in the Chapin method for tablets. 

Determination of Mercury and Iodin in Antiseptic Soaps, A. 
Seidell. 2 — About 10 grams of the soap is weighed into an Erlenmeyer 
flask and treated with 150 mils of 95 per cent alcohol and 3 to 5 mils con- 
centrated hydrochloric acid. The solution is warmed and successive 
small portions of water added until a perfectly clear solution is obtained 
on shaking. If suspended particles are present, the solution should be 
filtered. A slow stream of hydrogen sulphide is then passed through the 
liquid for about an hour, and the sulphide is collected on a carefully pre- 
pared Gooch crucible. The fatty material present in the solution appears 
to have a tendency to cause the precipitate to pass through the filter, but 
no trouble on this account need be experienced if care is taken to use the 
least amount of suction possible until the precipitate has been washed 
several times with 95 per cent alcohol. The sulphide is then washed with 
carbon disulphide, alcohol, and ether, dried at 100 to 105° and weighed. 

The filtrate and alcoholic washings from the sulphide are concentrated 
to about one-third, water added to replace the evaporated alcohol, the 
solution cooled and filtered from the separated fatty acids into a separatory 
funnel; 25 to 50 mils chloroform are added, the iodin liberated by the 
addition of a few drops of nitrous acid, and dissolved in the chloroform by 
shaking. The chloroform is then drawn off and a fresh portion added and 
shaken, and the procedure repeated until the whole of the iodin is removed. 
The combined chloroformic solutions are washed with water, and the 
washings shaken with fresh chloroform to recover any iodin which may 
have been taken up by them. Finally the chloroform solution is titrated 
with standard sodium thio sulphate. 

The nitrous acid solution is prepared by adding to a mixture of about 
10 grams of starch and 10 grams of arsenous acid contained in a 700-mil 
1 Pharm. J., 86, 405. 2 J. A. Chem. Soc, 1906, 28, 73. 



988 INORGANIC SECTION 

Erlenmeyer flask, about 150 mils nitric acid of 1.3 sp. gr. The solution 
is warmed gently and the reddish fumes conducted into a bottle contain- 
ing 100 mils of concentrated sulphuric acid. 

Determination of Mercuric Chloride in Surgical Dressings, R. Guiter. 1 
About 50 grams of the compound are mixed with about 250 mils of water 
in a 750-mil flask and well shaken for a few minutes; 5 grams of potassium 
iodide in solution are added and the whole shaken for ten minutes; 50 
mils of 10 per cent sodium hydroxide are then added, followed by 25 mils 
of 40 per cent formaldehyde; after shaking again, for ten minutes 12 mils 
glacial acetic acid are added and 15 mils of N/10 iodin; after shaking 
again for ten minutes the excess of iodin is determined by titration with 
N/10 sodium thiosulphate. 

Mercury in Organic Compounds 

The determination of mercury in organic combination can be effected 
by decomposing the organic matter with sulphuric and nitric acids and, 
after removing any residual nitric acid by evaporation, neutralizing with 
ammonia, precipitating the mercury as sulphide in presence of dilute hydro- 
chloric acid. If the circumstances warrant, the decomposition of the 
product may be effected in a Carius tube with fuming nitric acid, the heat 
being raised to a temperature of 160 to 180° for six to eight hours. After 
evaporating the solution, the residue is treated with dilute hydrochloric 
acid and the mercury precipitated as sulphide. 

Separation of Mercury from Other Metals. — Calomel may be separated 
from bismuth subcarbonate by dissolving out the latter with dilute hydro- 
chloric acid. The calomel is then collected on a Gooch, washed, dried, 
and weighed. If the tablet contains excipient insoluble in dilute acid, the 
calomel is then brought into solution with potassium iodide, precipitated 
with formaldehyde in presence of sodium hydroxide, and the precipitated 
mercury dissolved in acid and finally determined as sulphide, or dissolved 
in iodin solution in presence of acetic acid and the excess of iodin titrated. 

The bismuth in the filtrate is precipitated either as the trisulphide, 
carbonate, or chromate, as detailed under Methods for Determining 
Bismuth. 

Calomel and zinc sulphocarbolate are separated by dissolving out the 
zinc salt with water. 

Bismuth subnitrate is separated from mercury and chalk by solution 
in dilute hydrochloric acid. 

When mercury occurs with arsenic and iron, a solution of the sample 
acidulated with dilute hydrochloric acid, is precipitated with hydrogen 
sulphide. The filtrate contains the iron, which is converted into the 
ferric state, after boiling off the excess of hydrogen sulphide, and precipi- 

1 Pharm. Zeit. 1910, 427. 



METALS AND THEIR COMPOUNDS 989 

tated as hydroxide. The combined sulphides of mercury and arsenic are 
then digested with yellow ammonium sulphide, which dissolves the arsenic 
sulphide, and the residual mercury sulphide collected on a Gooch and, 
after the customary washing, weighed. 

Mercury can be separated from copper and arsenic by precipitation 
with phosphorous acid in presence of hydrochloric acid. The mixture 
is allowed to stand in the cold for twelve hours, at the end of which period 
the precipitated calomel is collected on a Gooch, washed with water, 
dried, and weighed. 

When mercury occurs with gold and arsenic, a solution of the sample free 
from nitric acid is treated with a clear freshly prepared solution of ferrous 
sulphate in the presence of a little hydrochloric acid, heated gently for a 
few hours until the precipitated fine gold has completely settled, filtered; 
and washed. The gold collecting on the filter, may be ignited and weighed, 
the filtrate subjected to the treatment with hydrogen sulphide, and the 
mercury separated from the arsenic as described above. 

Mercury can be separated from copper and arsenic by treating a solu- 
tion of the sample with 25 to 30 mils of saturated tartaric acid, stirring 
for one to two minutes, adding potassium cyanide in small amounts at a 
time until the solution becomes clear, stirring continually. The mercury 
is then precipitated with hydrogen sulphide in the cold. 

COPPER 

Copper salts are used in medicine because of their astringent, anti- 
septic properties and tonic values. They are used in remedies for diarrhea 
and other intestinal affections, for eye troubles, ringworm, ulcers, gonor- 
rhea, syphilis, and in remedies for diseases of poultry, especially roup. 
Copper sulphate and carbonate are antidotes in phosphorus poisoning. 
Copper oxide, CuO, is used internally for expelling tapeworm. The acetate, 
arsenite, nitrate, oleate, citrate, and phosphate are all used as remedial 
agents. The citrate is used in ointment form for eye troubles, and is 
recommended for trachoma. Nucleid of copper is known as cuprol. 

Copper arsenite is combined with calomel and morphin, and copper 
sulphate is combined with opium. 

The determination of copper may be accomplished electrolytically or 
volumetrically. In most medicinal preparations, copper is present in the 
form of an inorganic salt, and in order to remove the metal from extraneous 
substances, the sample should be warmed with dilute hydrochloric acid, 
filtered, and precipitated with hydrogen sulphide. The copper sulphide 
is then filtered, washed with water and dissolved in hot dilute nitric acid. 
The determination is finished either electrolytically or volumetrically. 

Electrolytic Estimation. — The solution obtained as above, described is 
collected in a beaker of about 250-mils capacity, and two platinum elec- 



990 



INORGANIC SECTION 



trodes lowered into the liquid, the anode being a length of platinum wire, 
and the cathode a platinum cone or crucible. A crucible, into the mouth 
of which is inserted a rubber stopper which in turn is connected with a 
rotating spindle, will give the best results. The apparatus described below 




FRONT ELEVATION 




SIDE ELEVATION 



will be found serviceable, and is indispensable to a well-equipped laboratory 
where it is necessary to perform a number of assays of copper or tin. 

A current of .5 and 1 ampere passed through the copper solution will 
give satisfactory results. The deposition of the copper is completed when, 
on lowering the spindle so that a clean surface of platinum is immersed, 
no further coloration appears. The crucible is then detached, washed with 



METALS AND THEIR COMPOUNDS 991 

distilled water, and alcohol and dried at 100° for a few minutes. The gain 
in weight is due to the metallic copper. 

Volumetric Estimation. — The hot solution is treated with sodium car- 
bonate solution 1 per cent until a slight permanent precipitate is formed. 
Acetic acid is added until the precipitate is dissolved and the solution is 
perfectly clear. The solution is cooled and potassium iodide added in 
considerable excess. Each 1 gram copper requires .527 gram potassium 
iodide and the solution should contain at least 1 gram in excess. As soon 
as the precipitated cuprous iodide has settled, the iodide is titrated with 
standard sodium thiosulphate. 

2(CH3COO) 2 Cu+4KI = 4CH3COOK+Cu 2 l2+l2 

The determination of copper in organic combination presents no serious 
difficulty as the organic matter can be destroyed, or at least separated 
from the copper, by digestion with sulphuric and nitric acid. This treat- 
ment is applicable to ointments. 

GOLD 

Auric chloride, AUCI3, is used as a remedy for consumption, tubercular 
affection, and lupus. A mixture of equal parts of gold chloride and 
sodium chloride (gold and sodium chloride U. S. P.) is used in syphilis, 
cancer, hysteria, neuralgia, and rheumatism, and is the form in which the 
metal is usually administered for the treatment of inebriety. Aurous 
iodide, Aul, and aurous cyanide and auric cyanide, Au(CN)3+3H20, are 
used in the treatment of scrofula and tubercular diseases. Aurous bromide 
and auric bromide are used as anodynes, nervines and anti-epileptics. 
Auric oxide, AU2O3, is an alterative, and is used in scrofula and tuberculosis. 
Potassium cyanaurate, KAu(CN)2, (gold and potassium cyanide) is an 
active antiseptic. Collaurin is a name given to colloidal gold. 

Gold salts are often present in treatments for the liquor and tobacco 
habits, and are combined with a variety of sedatives and narcotic drugs. 
In many of these remedies the quantity of gold present is exceedingly 
minute, and will usually be overlooked unless a special test is performed 
to establish its presence. 

Some of the combinations listed include pill formulas where gold and 
sodium chloride are present with the valerianates of zinc, iron, and quinin; 
with arsenous acid, with arsenic chloride, and quinin ■ with phosphorus, 
Nux Vomica, and damiana. 

Auric bromide is combined with bromides of arsenic and mercury in 
solutions. 

The quantity of gold in remedial agents is often so small that its pres- 
ence might easily be overlooked. In fact it may be necessary to perform 



992 INORGANIC SECTION 

special tests to determine its presence in many instances. Solutions con- 
taining gold salts are reduced by ferrous sulphate; weak solutions yielding 
a bluish coloration, stronger mixtures a brown precipitate. Oxalic acid, 
on being gently warmed with gold salts, causes the deposition of the metal, 
either as a scaly precipitate or as a coherent gold film. Stannous chlo- 
ride gives a precipitate or coloration (depending on the concentration) 
varying in color from reddish brown to purple. The presence of a trace 
of stannic chloride facilitates the production of the purple. 

U. S. P. Assay of Gold and Sodium Chloride. — .5 gram of the substance 
is dissolved in 25 mils of water in a porcelain dish, 5 mils potassium hydrox- 
ide added and 5 mils hydrogen peroxide. The mixture is heated for 
one-half hour on a water-bath, washed with water slightly acid with hydro- 
chloric acid, dried, ignited in a porcelain dish, and weighed. The residue 
should not be less than .15 gram, corresponding to at least 30 per cent 
of gold. 

To determine the gold in pills, the ground material should be boiled 
with aqua regia, the solution diluted if necessary to filter off any insoluble 
matter, and the clear filtrate evaporated on a water-bath to the consistency 
of syrup, adding from tune to time hydrochloric acid. The residue is dis- 
solved in water containing hydrochloric acid, and an excess of freshly pre- 
pared clear solution of ferrous sulphate added. It is then heated gently 
for a few hours until the precipitated gold has completely settled, filtered, 
washed, ignited in a porcelain crucible or dish, and weighed. 

If the sample contains iron which it is desired to determine subse- 
quently, or if it is important to have a filtrate free from this metal, the 
gold may be reduced by oxalic acid. The dilute solution, freed from 
nitric acid as above described, is mixed in a beaker with oxalic acid or 
ammonium oxalate in excess, sulphuric acid added and the beaker, covered 
with a watch-glass, is allowed to stand for two days in a moderately warm 
place. The separated gold is collected in a filter, washed and ignited. 
If the gold solution contains a large excess of hydrochloric acid, the latter 
should be for the most part evaporated before the solution is diluted and 
oxalic acid added. If chlorides of the alkali metals are present, it is 
necessary that the dilution be considerable, and the time of precipitation 
lengthened. 

BISMUTH 

The well-known salts of bismuth, the subnitrate and subgallate, are 
valuable remedial agents for inflammatory conditions of the mucous mem- 
brane, especially of the alimentary canal; the subgallate (dermatol) is 
used in the local treatment of eczema, ulceration and wounds in place of 
iodoform; and the organic combinations are usually employed where it 



METALS AND THEIR COMPOUNDS 993 

is desired to combine the soothing and protective actions of the bismuth 
with an antiseptic. Bismuth and ammonium citrate is astringent in 
action, and is the form in which bismuth is usually present in elixirs. 
Double citrates of bismuth and lithium and of bismuth and iron are 
soluble scale salts. 

The subnitrate and subcarbonate are dispensed in the form of pills, 
tablets, and powders, and the formulas often include the digestive ferments 
pepsin and pancreatin, with ginger and Nux Vomica. The subnitrate is 
also combined with calomel; with calomel and ipecac; with calomel, salol, 
and sodium bicarbonate; with cerium oxalate; with guaiacol carbonate; 
with camphor, opium, salol, and oil of peppermint; with charcoal; with 
opium and carbolic acid; with opium, Krameria, and licorice; with cerium 
oxalate and cocain. 

Bismuth subgallate will be found in a few tablet formulas with Nux 
Vomica and digestives, and in dusting powders. 

The elixir formulas containing bismuth and ammonium citrate will 
be found to contain in addition strj'chnin, the Cinchona alkaloids, ferric 
pyrophosphate, saccharated or lactated pepsin, and pancreatin. 

Bismuth salicylate has a limited use, principally in intestinal trouble. 

Milk of bismuth, or lac bismuth, is a suspension in water of a bismuth 
salt, usually the subcarbonate with more or less hydroxide. 

Bismuth oxide is prepared in colloidal form. It is sold under trade- 
mark names, " Bismon " being representative of the class. It forms an 
opalescent colloidal suspension with water, which is not precipitated by 
hydrogen sulphide unless acid is present. A solution of egg albumin 
produces a precipitate which dissolves in excess of the albumin solution. 

Tannismuth is bitannate of bismuth, containing between 17 and 21 
per cent of bismuth. 

Bismuth betanaphtholate, known as Orphol, is a brownish or grayish 
powder insoluble in water and chloroform, and slightly soluble in alcohol. 
It is gradually decomposed on shaking with mineral acids, and the naphthol 
may be recovered by shaking out with chloroform. For assaying the salt, 
the following procedure is used : 

From 1 to 2 grams are shaken in a separator during one hour with 
25 mils chloroform, and 25 mils concentrated hydrochloric acid; 50 mils 
of water are then added, and the mixture again shaken. The chloroform 
layer is then drawn off, the acid solution shaken with three portions of 
10 mils of chloroform, and the combined extracts evaporated and dried 
over sulphuric acid, the weight amounting to at least 15 per cent. The 
acid solution is transferred to a beaker, diluted with water to 200 mils, 
heated to boiling, ammonia added until a turbidity appears, then sufficient 
hydrochloric acid to clear up the turbidity, and finally 50 mils of 10 per 
cent ammonium phosphate. When the precipitate has subsided the clear 



994 INORGANIC SECTION 

liquid is decanted through a tared, ignited Gooch crucible, the precipitate 
washed by decantation with boiling water and finally transferred com- 
pletely to the Gooch. It is then dried, suspended in a nickel crucible, and 
exposed to the full heat of the Bunsen flame until the weight is constant. 
The weight of the bismuth phosphate multiplied by .6869 should yield a 
figure representing metallic bismuth, equal to not less than 60 per cent 
of the material taken. 

Crurin is quinolin-bismuth sulphocyanate (C9H7N-HSCN)3Bi(SCN)3. 
It is a bluish-red substance, insoluble in alcohol and ether, but soluble 
in acetone, and slightly in glycerin. It is decomposed by water. It dis- 
solves in dilute nitric acid, yielding a solution from which bismuth can 
be precipitated with hydrogen sulphide, and in which the sulphocyanide 
content can be determined by titration with standard silver nitrate. 

Airol— Bismuth Oxyiodogallate. Airoform, C 6 H 2 (OH) 3 (COOBiI(OH) ) 

is a combination of bismuth oxyiodide (subiodide) and gallic acid. It 
is prepared by heating molecular quantities of bismuth subgallate and 
hydriodic acid or bismuth oxyiodide and gallic acid, in the presence of 
water, until a grayish-green product results, which is drained and dried. 

It is a voluminous grayish-green, odorless, and tasteless powder, insolu- 
ble in alcohol, ether, chloroform, and olive oil, slightly soluble in glycerin. 
It is practically insoluble in water, communicating to water a red color on 
standing, slowly in the cold, but readily when heated, being decomposed 
with liberation of iodin and bismuth subgallate. It is readily soluble, 
with decomposition, in dilute alkalies and mineral acids. It is decomposed 
on exposure to moist air, turning red, but in admixture with glycerin and 
a little water it long remains unaltered. 

Bismal, 4(Ci 5 Hi 2 Oio), 3Bi(OH) 5 

is a compound of bismuth hydroxide and methylendigallic acid. 

It is obtained by digesting 4 molecules of methylendigallic acid with 
3 molecules of bismuth hydroxide in water. 

It is a voluminous gray-brown powder, insoluble in water or gastric 
juice, but soluble in alkalies, forming yellowish-red solutions. 

Xeroform-Tribromphenol-Bismuth 

Xeroform is basic bismuth tribrom-phenolate, Bi(C6H 2 Br30)20H • Bi 2 03, 
containing nearly 50 per cent of B12O3. 

According to the patent it is obtained by dissolving tribromphenol 
in sodium hydroxide and adding bismuth nitrate to the sodium tribrom- 
phenolate solution. The precipitated tribromphenol bismuth is collected, 
and washed with alcohol. 



METALS AND THEIR COMPOUNDS 995 

It is a fine yellow, nearly odorless and tasteless powder, neutral in 
reaction, and unaffected by light. It is insoluble in water, alcohol, chloro- 
form liquid petrolatum, and vegetable oils, but soluble in 2 per cent, 
hydrochloric acid in the proportion of 30 : 100. By alkalies it is decom- 
posed with the formation of bromides; it is not decomposed by heat at 
temperatures below 120° C, and therefore may be sterilized. 

It should yield 49.5 per cent of bismuth oxide. If 1 gram is boiled 
with sodium hydroxide T. S. filtered, the filtrate rendered acid with sul- 
phuric acid and the white, curdy precipitate washed and dried, it should 
melt at 95° C. (tribromphenol) . 

Bismutol is bismuth and sodium phosphosalicylate. 

Helcosol is a basic compound of bismuth and pyrogallol, a yellow 
amorphous powder soluble slightly in very dilute hydrochloric acid, 
insoluble in water and alcohol. 

Dermol is a combination of bismuth and chrysophanic acid, probably 
a basic salt. It is a yellow amorphous powder, insoluble in water and 
alcohol, but dissolving in nitric or sulphuric acids. 

Biodal is stated to be monoiododibismuthmethylenedicresotinate. 
It is a pink, odorless, tasteless, insoluble powder. 

Bismutose is a bismuth-albumin compound soluble in alkalies and 
slightly in dilute acids, but insoluble in water. 

Assay of Bismuth Salts. — The bismuth content of bismuth subnitrate 
and subcarbonate is determined by igniting the sample in a porcelain 
crucible to constant weight. The Bi2C>3 in the subnitrate amounts to 
not less than 79 per cent and in the subcarbonate not less than 90 per cent. 

Organic salts are ignited in the same way until there is no further 
change in the appearance of the blackened residue. The crucible is cooled 
a few drops of concentrated nitric acid added, the acid evaporated over 
the steam-bath, and the residue carefully ignited to constant weight. 

Determination of Bismuth in Mixtures. — Bismuth is determined in 
elixirs or in solutions of its soluble salts by evaporating the sample to 
dryness in a porcelain dish and igniting. The residue is then treated with 
concentrated nitric acid, and after the reaction due to solution of the bis- 
muth or its oxide has ceased, the contents of the dish are warmed on the 
steam-bath, diluted sufficiently to prevent the acid from acting on filter 
paper, but not until the basic bismuth salt is thrown out; the solution 
filtered and washed with warm dilute nitric acid Ammonium carbonate, 
is added in very slight excess, heated nearly to boiling for some time, 
filtered onto a tared Gooch, washed with water, dried and ignited to con- 
stant weight. 

When iron accompanies bismuth, the procedure should be modified. 
The ignited residue is dissolved in nitric acid, filtered, and evaporated 
until the excess of acid is drawn off. The residue is dissolved in sufficient 



996 INORGANIC SECTION 

hydrochloric acid to hold up the oxy chloride of bismuth, and subjected 
to the action of hydrogen sulphide until the bismuth is completely pre- 
cipitated. The sulphide of bismuth is then collected on a filter and well 
washed with water, the filtrate and washings being preserved, if desired, 
for the subsequent determination of the iron. The filter paper and sul- 
phide of bismuth are then transferred to a beaker, treated with diluted 
nitric acid 1-1 and heated until the bimuth is dissolved. The solution 
is filtered, washing through the filter with dilute nitric acid, the filtrate 
and washings precipitated with ammonium carbonate, and the determi- 
nation completed as above described. 

The bismuth content of the milk of bismuth preparations can in most 
instances be determined by evaporating off the water, igniting the residue, 
and weighing the bismuth oxide. If the composition is unusual, or 
impurities occur in the bismuth precipitate, it may be necessary to dissolve 
the basic salt in hydrochloric acid and precipitate with hydrogen sulphide, 
completing the determination in the usual way. 

Powders containing bismuth salts in combination with digestives, 
antiseptics, and sodium bicarbonate should first be ignited to decompose 
the organic matter. The bismuth salt is then dissolved out with nitric 
acid and determined as usual. 

In powders or tablets with calomel, bismuth salts are determined by 
first dissolving them in diluted hydrochloric acid in order to separate them 
from the calomel. The bismuth is thrown out of the filtrate as sulphide, 
and the determination continued. 

When bismuth salts occur in complex tablet mixtures, the determi- 
nation of the metal can usually be effected by burning off the organic matter 
by gentle ignition, treating the residue with concentrated nitric acid, and 
continuing to the procedure for elixirs. If zinc or other heavy metals 
are present, it will be necessary to evaporate the nitric acid solution to 
dryness, dissolve the residue in diluted hydrochloric acid, and throw out 
the bismuth as sulphide. 

Bismuth may be determined as the trisulphide, by collecting the pre- 
cipitated sulphide on a tared Gooch, washing with water, alcohol, ether, 
carbon bisulphide free from sulphur and finally alcohol and ether. The 
Gooch is then placed in a drying oven at 100° for fifteen to twenty minutes, 
cooled in a desiccator and weighed. There should be as little exposure as 
possible to the air at 100° C, as the sulphide absorbs oxygen and gains in 
weight Bi 2 S3X.9061 = Bi 2 O3. 

Bismuth can be determined by precipitation as phosphate as described 
in the Assay of Orphol. 

The formation of the chromate furnishes a satisfactory means of 
determining bismuth. The bismuth is freed from other substances by 
the methods described above, and a solution which is as neutral as possible 



METALS AND THEIR COMPOUNDS 997 

is poured, with constant stirrng, into an excess of a warm solution of 
potassium bichromate in a porcelain dish, washing out the vessel which 
contained the bismuth solution with water containing nitric acid. The 
precipitate should be orange yellow and dense throughout; if it is floc- 
culent and has the color of egg yolk, there is a deficiency of bichromate 
and a fresh quantity of the latter must be added, and the mixture boiled 
until the precipitate has the proper appearance. The mixture is boiled 
for ten minutes and the clear supernatent liquid decanted through a tared 
Gooch; the precipitate is boiled with water, repeatedly decanting the 
washings through the Gooch, and finally collected on the filter. It is 
dried at 120° and weighed as Bi2(V2Cr03. 

Bismuth in Bismuth-/3-Naphtholate-Electrolytic Determination, 
Murray. 1 — A sample of .3 gram is weighed into a porcelain crucible and 
heated very gently to decomposition of the 0-naphthol. The crucible 
is finally heated to the full red heat of a Meker burner for three minutes 
to burn off the last traces of carbon. The residue resulting is j^ellow in 
color and is composed chiefly of bismuth oxide together with a small 
quantity of metallic bismuth. The crucible is placed in a small beaker 
and a mixture of 4 mils of nitric acid (sp. gr. 1.4) and 5 mils of water is 
added, after which it is heated on a steam-bath to complete solution. 
The solution is washed with distilled water into a mercury cathode cup, 
keeping the volume down to 20 mils. The cathode cup is conveniently 
made from a 50-mil Erlenmeyer flask. The 20 mils solution is then 
electrolyzed under the following conditions: 

Current (maximum) 4.5 amperes at 6 volts. 

Revolutions per minute 1000. Tune forty-five minutes. 

The initial application of the current is 1 ampere and this is followed 
by a gradual increase to 4.5 amperes. Some black masses are seen to 
form, but rapid rotation of the anode prevents the formation of a large 
quantity and all disappear, when the black masses have stopped and 
the cathode is washed with distilled water by siphonation while the full 
strength of a current is on. The electrolyte should be tested for bismuth 
with hydrogen sulphide. After two to three washings with water, followed 
by alcohol and then by ether, the mercury cathode is weighed. The 
increase in the weight of the mercury cathode is due to the bismuth which 
has been deposited on and amalgamated with the mercury. 

ARSENIC 

Arsenous oxide is one of the ingredients of alterative, tonic and anti- 
periodic remedies which are prescribed in intermittent fever, chorea, 
chronic rheumatism, chronic syphilitic and cancerous diseases, etc. It 
1 J. Ind. and Eng. Chem., i, 1916, 258. 



998 INORGANIC SECTION 

is dispensed alone, and often in combination in pills and tablets with 
reduced iron, ferrous carbonate, strychnin, and quinin. Some of the other 
combinations of arsenous oxide include the following, with chinoidin, 
oleoresin pepper, and iron ferrocyanide (anti-chill mixture) ; with quinin, 
ferrous sulphate, Gelsemium resin, Podophyllum resin, and oleoresin pep- 
per; with powdered black pepper, acacia, and althea; with quinin, oleo- 
resin of Capsicum, zinc oxide, and strychnin; with extract of Eucalyptus, 
chinoidin, iron ferrocyanide, and Capsicum (fever and ague) ; with quinin, 
morphin, strychnin, and aconite; with quinin, Taraxacum, and ferrous 
sulphate; with Sumbul, asafetida, and ferrous sulphate; with quinin, 
strychnin, ipecac, and reduced iron; with extract Cannabis sativa and 
reduced iron; with ferrous carbonate, strychnin, and Hyoscyamus; with 
strychnin, ferrous sulphate, mercuric chloride, and potassium carbonate; 
with quinin, acetanilid, strychnin, Hyoscyamus, and Cannabis sativa; 
with ferrous sulphate, valerian, Sumbul, and asafetida; with sulphur, 
potassium bitartrate, sodium benzoate, ipecac, and Capsicum; with 
quinin, strychnin, gentian, and reduced iron; with quinin, ferric chloride, 
gold, and sodium chloride; with ferrous carbonate, Nux Vomica, and 
Cascara; with quinin, reduced iron, strychnin, and Cascara. 

Arsenous oxide is sold in capsule form with cod-liver oil, creosote, 
atropin, and strychnin. 

In the elixir form it is combined w r ith iron pyrophosphate and quinin 
sulphate. 

Solution of arsenous acid U. S. P. is a 10 per cent solution of arsenous 
oxide in dilute hydrochloric acid. 

Fowler's solution or solution potassium arsenite is prepared by dis- 
solving arsenous oxide and potassium bicarbonate in water, and adding 
compound tincture of lavender. 

Arsenous oxide is a component of rat poisons. 

Arsenic tribromide or arsenous chloride is recommended in diabetes, 
and is used alone and in combination with bromides of gold and mercury. 
Clemens' solution is prepared by adding bromin to a solution of potas- 
sium arsenite containing 1 per cent AS2O3. The title " solution of bromide 
of arsenic," which is often applied to some of the preparations, is some- 
what misleading, as arsenic bromide is decomposed by water into hyclro- 
bromic and arsenous acids. 

Pearsons' solution is a 1/10 per cent solution (approx.) of sodium 
arsenate. Arsenous chloride is found in tablets combined with the chlo- 
rides of ammonium and iron and quinin hydrochlorate; and with the 
chlorides of iron and mercury and quinin hydrochlorate. 

Arsenous iodide is used internally for the treatment of skin diseases, 
and externally as an ointment for the reduction of tubercular swellings. 
It is combined with mercuric and ferrous iodides ; with the iodides of mer- 



METALS AND THEIR COMPOUNDS 999 

cury, iron, and potassium, mercuric chloride, and Nux Vomica. Dono- 
van's soution is a 1 per cent aqueous solution of arsenous and mercuric 
iodides. 

Arsenous sulphide is used internally for diseases of the skin. 

Arsenic peptonate is often found in combination with the peptonate 
mixtures of iron and manganese. 

In a discussion of the organic substances containing arsenic in combi- 
nation the analyst is referred to the chapter on page 873. 

Arsenous oxide is assayed according to the Pharmacopoeia by treat- 
ing .1 gram with 1 gram sodium bicarbonate, dissolving in 20 mils water 
with the aid of gentle heat, and titrating with N/10 iodin, of which not 
less than 20.3 mils should be required. 

For the assay of the solution arsenous acid, 24.6 grams are treated 
with 2 grams sodium bicarbonate and 100 mils water and titrated with 
N/10 iodin, of which not less than 50 mils should be required. 

For the assay of Fowler's solution 24.6 grams are diluted with water 
to 100 mils, slightly acidified, then made alkaline with sodium bicarbo- 
nate, and titrated with N/10 iodin, of which not less than 50 mils should 
be required. 

The arsenous oxide in rat powders can be estimated by weighing out 
from .2 to 5. gram, mixing with 1 to 2 grams sodium bicarbonate and 
transferring to a 100-mil graduated flask with 25 mils water, the flask is 
warmed gently, but not sufficiently to gelatinize any starch which may 
be present. After thoroughly shaking, the contents are made up to 100 
mils, and aliquots of 10 to 25 mils filtered off and titrated with N/10 iodin. 

The estimation of arsenic in pills, tablets, and other mixed remedies, 
may be conducted as described in the chapter on General Methods. 

When iron occurs with arsenic, and this is usually the case with medi- 
cinal preparations, the advisability of depending absolutely on the evolu- 
tion determination may become a matter of moment, as it has been claimed 
that iron holds back some of the arsenic. This question is almost certain 
to come up in court, if the method has been used in the analysis of the 
preparation on which the case is based. It is probable that one will 
obtain all of the arsenic in the mirror from a given quantity of aliquot 
taken, provided he runs the determination over a sufficiently long period, 
and the aliquot used does not contain too much arsenic. It is advisable 
to run several determinations with the same solution, using different 
amounts, say 5, 10, 15, 20-mil portions, and note whether they check 
or not. As a confirmatory measure and when it is desired to determine 
the amount of iron present the solution containing the metals, free from 
organic matter, is neutralized with alkali and acidulated with hydro- 
chloric acid. Hydrogen sulphide is passed through the mixture, which 
is kept warm during the treatment, until the arsenic is entirely precipi- 



1000 INORGANIC SECTION 

tated. The precipitation will be slow at first, as all of the arsenic is in the 
higher state of oxidation. When there is apparently no further precipi- 
tation of arsenic sulphide and sulphur and the liquid is well saturated with 
the gas, it is well to stopper the container and allow it to digest overnight. 
The sulphide and sulphur are then collected on a filter, well washed with 
water, and the filtrate and washing set aside for the iron determination. 
The filter is transferred to a beaker, covered with strong nitric acid, and 
heated until the sulphide has dissolved and most of the sulphur has been 
oxidized. The solution is somewhat diluted, a crystal or two of potassium 
chlorate added, and gently warmed until the odor of the gas has nearly 
disappeared. The solution is filtered, washed with water, the filtrate 
and washings treated with ammonia which must produce no precipitate 
or turbidity. An excess of magnesia mixture is added gradually with 
constant stirring and the solution allowed to stand at least twenty-four 
hours, after adding a further quantity of ammonia. The ammonia- 
magnesium arsenate is collected on a filter, washed with a mixture of 
ammonia and water 1 in 3. After drying the precipitate is transferred 
to a porcelain crucible, the filter burned and the ash added to the contents 
of the crucible, and the whole ignited to constant weight. Mg2As2C>7. 

ANTIMONY COMPOUNDS 

Antimony salts have long been used in medicine, and some of the 
old-time preparations which are obsolete for the treatment of human 
beings are employed in veterinary practice. 

Antimony and potassium tartrate or Tartar Emetic is the salt most 
commonly employed as a medicinal agent, and is present in expectorant 
diaphoretic, alterative, and emetic compounds. Some of the more impor- 
tant formulas consist of this salt with mass of mercury, aloes and jalap 
(Cole's dinner pills); with ammonium chloride and Hyoscyamus; with 
ammonium chloride, morphin and Sanguinaria; with morphin and aconite; 
with morphin, aconite, and ipecac; with licorice, benzoic acid, opium, 
camphor, and anise oil; with ammonium chloride, senna, licorice, and 
sulphur; with ipecac, Sanguinaria, morphin, atropin, and aconite. 

Wine of antimony is a solution of. tartar emetic in wine; and compound 
syrup of Squill contains senega and tartar emetic. 

Tartar emetic is a component of a certain type of plaster designed to 
produce the pustulating effect of the emetic. The base of these plasters 
is usually Burgundy pitch and colophony. 

Sulphurated antimony or Kermes minerals is a mixture of sulphides 
and oxides of the metal. It is used as an alterative, diaphoretic, and 
emetic. Plummer Pills, a classic formula, contains Kermes mineral, 
calomel, and guaiac. It is also combined with ipecac and morphin; and 
with aconite, bryonia, belladonna, and potassium bichromate. 



METALS AND THEIR COMPOUNDS 1001 

Antimonial saffron, Crocus Metallorum, consists chiefly of antimony 
oxysulphide, Sb 2 S 3 +Sb 2 OS 2 . 

Antimony sulphide, SD2S3, and antimonic sulphide, SD2S5, the golden 
sulphide, are used in veterinary remedies. 

Antimonous oxide, SD2O3, is an expectorant and emetic, and is the 
active constituent of Antimonial powder or James' Powder (Pulvis Jacobi), 
a mixture with precipitated calcium phosphate. 

Antimony chloride, SbCl3, is used as a local application for snake 
bites, wounds, syphilitic ulcers, warts, and excrescences. 

Antimony iodide, Sbl3, is employed in catarrh. 

Antimony, when present in simple mixtures or alone as antimonous 
oxide, as for instance in James' powder, can be determined by titration 
with iodin. The powdered material amounting to about 2 grams is weighed 
accurately, introduced into a 250-mil graduated flask, treated with 2 
grams of tartaric acid dissolved in 25 mils water, and the mixture shaken 
gently for sufficient time to dissolve the oxide. Sodium carbonate is 
added until the solution is just neutral, and the liquid made up to 250 mils. 
After settling, a 50-mil aliquot is drawn off into a flask and titrated with 
N/10 iodin. 1 mil = .0072 gram Sb 2 3 . 

Sb203+2H 2 0+2l2 = HI+Sb 2 05 

When antimony salts are present in pills or tablets, the sample should 
be well pulverized, introduced into a 250-mil graduated flask, covered 
with concentrated hydrochloric acid and warmed. When ebullition 
ceases, the solution is made up to the mark with 5 per cent tartaric acid 
solution and after settling, aliquots of 5 mils are drawn off, heated nearly 
to boiling, and hydrogen sulphide conducted through the liquid, keeping 
the liquid fairly hot during the passage of the gas. When thoroughly 
saturated, the flask is stoppered and allowed to remain in a warm place 
overnight. It may sometimes happen, where the quantity of antimony 
is small, that no precipitate will appear until the mixture has stood for 
some time. The sulphide is then collected on an ashless filter, washed 
with hydrogen sulphide water, and the filter and precipitate transferred 
to a tared porcelain crucible with concave lid. About eight to ten times 
the quantity of fuming nitric acid is added and the acid slowly evapo- 
rated on the water-bath. If charring occurs after the nitric acid has 
evaporated, a few more drops of the latter are added, and the evapora- 
tion repeated, and the procedure continued until no further blackening 
occurs. The residual mass in the crucible consists of antimonic and sul- 
phuric acids, and on careful ignition is converted to antimony tetroxide, 
Sb 2 4 . 

If the sulphide of antimony carries down much sulphur, the precipi- 
tate on the filter should be washed with alcohol, ether, and carbon bisul- 



1002 INORGANIC SECTION 

phide, and then with alcohol before being subjected to the acid 
digestion. 

If mercury is simultaneously present, the sulphide precipitation may 
contain mercury, and in this event the filter paper containing the mixed 
sulphides is spread out in a porcelain evaporating dish and digested with 
yellow ammonium sulphide. The sulphide solution containing the anti- 
mony is filtered off, the digestion repeated and the combined filtrates 
and washings are treated with an excess of hydrochloric acid. The pre- 
cipitated antimony sulphide is collected on a filter and the balance of the 
determination completed as described above. 

NICKEL 

The only nickel salt that has ever attained any importance in medi- 
cinal chemistry is the bromide which is employed as an antispasmodic. 
As it is of unusual occurrence it might be overlooked unless the label 
of the preparation indicated its presence. It is usually combined with 
codein. 

A determination of the halogen is the simplest method of estimating 
nickel bromide. The metal may be determined by precipitating as hydrox- 
ide with potassium or sodium hydroxide. A solution of the salt is treated 
with an excess of the alkali and heated for some time nearly to boiling. 
The supernatant liquid is decanted, the hydroxide boiled up three or four 
times with water, decanting each time, and then brought onto the filter 
and thoroughly washed. After drying, the precipitate is ignited in a 
porcelain crucible and weighed as nickelous oxide, MO. Instead of 
weighing as the oxide the latter may be reduced to the metal by ignition 
in a slow stream of hydrogen. The heat is applied gently at first and 
then more strongly until a constant weight is obtained. 

With some mixtures it will be better to separate the nickel first as sul- 
phide. A concentrated solution should be treated with ammonium 
chloride until nearly saturated, ammonia added until slightly alkaline, 
then acetic acid in slight excess. Ammonium or sodium hydroxide are 
then added, and the hydrogen sulphide passed through the boiling solution. 
If there is considerable nickel present and hence more than a small amount 
of acetic acid liberated, it will be necessary partially to neutralize during 
the process. Filter the sulphide, test the filtrate with a few drops of 
ammonium sulphide to determine whether the nickel has been completely 
thrown out, wash the precipitate with dilute hydrogen sulphide water, 
and dry. The precipitate is then transferred to a beaker, the filter inciner- 
ated in a porcelain crucible and the ash added to the beaker, aqua regia 
added, digested at a gentle heat until the sulphide is dissolved, and the 
undissolved sulphur appears yellow; the liquid is then diluted, filtered, 
and the nickel precipitated as hydroxide as described above. 



METALS AND THEIR COMPOUNDS 1003 

If iron is present it may be removed before precipitating the nickel 
for its final determination, by adding ammonium chloride, and warming, 
adding ammonia in excess and digesting for several hours. Nickel will 
remain in solution. After filtering and washing, the ferric hydroxide 
should be dissolved in hydrochloric acid and precipitated again under the 
same conditions as before, adding the filtrate to that first obtained. The 
operation should be repeated a third time. The combined filtrates are 
then concentrated and the nickel determined as described. 

IRON 

Iron is used in medicine in the form of metallic or reduced iron; in 
the, ferrous state (ferrous carbonate in Blaud's mass and Vallet's mass, 
and ferrous iodide), in the ferric state (ferric chloride); and in complex 
combinations. In the latter the iron does not respond to the usual 
reactions until the compound has been subjected to the action of a reagent 
capable of breaking up the complex form. 

Solutions of ferric salts are used externally as styptics, and as astrin- 
gents in gargles, but the principal use of iron is for the treatment of anemia, 
chlorosis, and conditions where a tonic or alterative is desired. 

Iron salts will be encountered in several different types of pharmaceu- 
tical combinations, including pills, tablets, elixirs, wines, syrups, solu- 
tions, capsules, and gargles. The formulas are legion. The detection 
of iron presents no difficulties, and if present in a preparation, it will 
unquestionably be found during the course of the systematic analysis. 
The analyst may be called upon to determine the state in which the iron 
exists, as this feature may, in some cases, determine the efficacy of the 
medicine and also the claims set forth on the label. It is not enough to 
report that iron is present and its percentage amount given, the analyst 
should know whether it is in the ferrous or ferric state, and how much 
of each form exists as the preparation is administered. 

Vallet's mass consists of ferrous carbonate which has been washed 
free of sodium carbonate and preserved with a saccharin mixture. Blaud's 
mass prepared with potassium carbonate, contains all of the potassium 
sulphate produced by the reaction with ferrous sulphate. Ferrous car- 
bonate saccharated, prepared by precipitating the iron with sodium bicar- 
bonate, consists of the ferrous salt intimately mixed with sugar. 

Iron preparations often contain other metallic salts from which the 
metal must be separated in making a quantitative estimation, and phos- 
phates are sometimes present, thereby complicating the analysis, and, 
in some cases, rendering a quantitative determination difficult or impos- 
sible. 

The separation of iron from the metals of the arsenic and copper groups 
is of course easily effected, as these bodies are removable by hydrogen 



1004 INORGANIC SECTION 

sulphide, in presence of dilute hydrochloric acid, leaving the iron still 
dissolved. Iron being precipitated by ammonia in presence of ammonium 
chloride, can be separated from the alkali metals and the alkaline earths 
unless phosphates are present, in which case the alkaline earths compli- 
cate matters by precipitating simultaneously. Of its own family, the only 
metal of any importance accompanying iron is manganese. 

With many preparations, especially syrups and elixirs, it is possible 
to determine iron in the same sample that has been used for determining 
the alkaloids. With pills and tablets the organic substances can be dis- 
solved out with alcohol, leaving the iron salts behind for subsequent 
treatment dependent on the results of the qualitative investigation. Ferric 
chloride is of course soluble in alcohol, but this salt is seldom found except 
in solution, though it is combined with antipyrin as ferropyrin. 

Assay of Ferrous Carbonate Saccharated. — Dissolve about 2 grams 
of saccharated ferrous carbonate, accurately weighed, in 15 mils of diluted 
sulphuric acid, and dilute the solution with distilled water to about 100 
mils. Titrate immediately with N/10 potassium dichromate V. S., potas- 
sium ferricyanide T. S. being used as indicator. It shows not less than 
15 per cent of FeCC>3. 

Each mil of N/10 potassium dichromate V. S. used corresponds to 
.011584 gram of FeCOs. Each gram of saccharated ferrous carbonate 
corresponds to not less than 13 mils of N/10 potassium dichromate V. S. 

Reduced Iron — Assay for Metallic Iron. — Introduce about 2.6 grams 
of iodin into a 100-mil glass-stoppered graduated flask, weigh accurately, 
add 6 mils water, 2 grams potassium iodide and .555 gram reduced iron. 
Stopper the flask, and after thoroughly mixing the contents by rotating, 
set aside for one hour. Then dilute the contents with distilled water 
and make the liquid measure exactly 100 mils when cool, mix well, draw 
off 25 mils of this solution and titrate with N/10 sodium thiosulphate. 
Divide the weight of the iodin taken by .02518, subtract from the quotient 
twice the number of mils of N/10 thiosulphate used; the remainder repre- 
sents the percentage of metallic iron present in reduced iron and this 
should not be less than 90 per cent. 

The percentage purity of the iodin should be accurately determined, 
and in place of the 2.6 grams above directed, its equivalent of pure 100 
per cent iodin may be taken. 

Determination of Ferric Iron. — Ferric iron is easily determined by 
taking advantage of the reaction occurring in potassium iodide solution 
containing hydrochloric acid. The liberated iodin is titrated with N/10 
sodium thiosulphate, 1 mil of which is equivalent to .00555 gram iron. 
A weighed amount of the salt or liquid to be tested is weighed into a glass- 
stoppered bottle of about 100-250 mils capacity, 2 mils of hydrochloric 
acid, a proper quantity of water and 1 to 2 grams potassium iodide. The 



METALS AND THEIR COMPOUNDS 



1005 



mixture is kept for one-half hour at 40° C, then cooled and the iodin 
titrated. 

U. S. P. PRODUCTS BY THE ABOVE METHOD 









Hydro- 


Potas- 




Product 


Sample used 


Water, 
mils 


chloric 
Acid, 
mils 


sium 
Iodide, 
grams 


Standard 


Ferric chloride 


1 gram dry 
.555 gram 


100 


3 


2 


Not less than 22 mils 


Ferric citrate 


15 


2 


1 


Not less than 16 mils 


Ferric and ammonium citrate. . 


.555 gram 


15 


2 


1 


Not less than 16 mils 


Ferric and ammonium sulphate 


.555 gram 


15 


2 


1 


Not less than 11.5 mils 


Ferric and ammonium tartrate 


.555 gram 


15 


2 


1 


Not less than 13 mils 


Ferric and potassium tartrate. . 


.555 gram 


15 


2 


1 


Not less than 15 mils 


Ferric and quinin citrate (see 












assay following) 


.555 gram 




3 


1 


Not less than 13.5 mils 


Ferric and strychnin citrate 












(see assay following) 


1.11 




4 


1 


Not less than 32 mils 


Ferric phosphate 


.555 


10+40 


2 


1 


Not less than 12 mils 


Ferric phosphate (soluble) .... 


.555 


10+40 


8 


2 


Not less than 10 mils 


Solution of ferric chloride 


10 mils di- 
luted to 
100 and 
11.1 mils 












taken 


10 


2 


1 


Not less than 20 mils 


Solution of ferric sub-sulphate . 


10 mils di- 
luted to 
100 and 
11.1 mils 












taken 


10 


> 


1 


Not less than 27. 15 mils 


Solution of ferric sulphate 


1.11 


15 


2 


1 


Not less than 20 mils 



Colorimetric Estimation of Iron, J. S. Mayer. 1 — The originator of this 
method recommends it especially for assaying beef, iron, and wine, and 
other iron protein mixtures. 

Ten mils beef, iron, and wine are diluted with distilled water to 500 
mils; 5 mils of this solution are evaporated and ignited in a platinum 
dish, 5 mils hydrochloric acid (1-1) added, the mixture boiled an instant, 
poured into a 100-mil Nessler tube, water added to 100 mils, 3 drops 
potassium permanganate (5-1000) added to oxidize the iron, and after 
a few minutes 10 mils of potassium thiocyanate (20-1000) added, the 
color produced being immediately compared with iron standards. 

Multiply the reading of the standard tube by 100 and the result will 
be milligrams of iron per 100 mils of sample. 

The iron standards are made up according to the method of D-. D. 
1 J. Amer. Pharm. Assn., 1916, 5, 517. 



1006 INORGANIC SECTION 

Jackson, by mixing definite quantities of two solutions, one containing 
potassium platinic chloride and the other cobaltous chloride. 

ASSAY OF IRON AND QUININ CITRATE 

Assay for Quinin. — Introduce 1.11 grams of the salt into a dish, and, 
with the aid of a gentle heat, dissolve it in 20 mils of water. Transfer 
the solution, together with the rinsings of the dish, to a separator, allow 
the liquid to become cold, then add 5 mils of ammonia water and 10 mils 
of chloroform, and shake the separator for one minute. Allow the liquids 
to separate, draw off the chloroformic layer, and shake the residuary 
liquid a second and a third time with portions of 10 mils each of chloro- 
form. Allow the combined chloroformic solutions to evaporate spon- 
taneously in a tared dish, and dry the residue at 100° C. to a constant 
weight. This residue should weigh not less than .1276 gram (correspond- 
ing to at least 11.5 per cent of dried quinin). 

Assay for Iron. — Heat the aqueous liquid, from which the quinin 
has been removed in the manner just described, on a water-bath, until 
the odor of chloroform and of ammonia have disappeared, allow it to cool, 
and dilute it with water to the volume of 50 mils. Transfer 25 mils of 
the liquid to a glass-stoppered flask having the capacity of about 100 mils, 
add 3 mils of hydrochloric acid and 1 gram of potassium iodide, and after 
securely closing the flask, allow the mixture to stand for half an hour at 
40° C. After it has been allowed to cool, it should require not less than 
13.5 mils of N/10 sodium thiosulphate to discharge the color of the liquid, 
starch being used as indicator (each mil of the N/10 sodium thiosulphate 
indicating 1 per cent of metallic iron), 

ASSAY OF IRON AND STRYCHNIN CITRATE 

Assay for Strychnin. — Dissolve 4.44 grams of the salt in a separator, 
in 15 mils of water, add 5 mils of ammonia water, 10 mils of chloroform, 
and shake the separator for one minute. Allow the liquids to separate, 
draw off the chloroformic layer, and shake the residuary liquid a second 
and a third time with portions of 10 mils each of chloroform. Allow 
the combined chloroformic liquids to evaporate spontaneously in a tared 
dish, and dry the reside at 100° C. to a constant weight. This residue 
should weigh not less than .04 (.0399) gram, nor more than .0444 gram 
(corresponding to not less than .9 nor more than 1 per cent of strychnin). 

Assay for Iron. — Heat the aqueous liquid, from which the strychnin 
has been removed in the manner just described, on a water-bath, until 
the odors of chloroform and of ammonia have disappeared, allow it to 
cool, and dilute it with water to the volume of 100 mils. Transfer 25 
mils of the liquid to a glass-stoppered flask having the capacity of about 



METALS AND THEIR COMPOUNDS 1007 

100 mils, add 4 mils of hydrochloric acid and 1 gram of potassium iodide, 
and after securely closing the flask, allow the mixture to stand for half 
an hour at 40° C. After it has been allowed to cool, it should require not 
less than 32 mils of N/10 sodium thiosulphate to discharge the color 
of the liquid, starch being used as indicator (each mil of N/10 sodium 
thiosulphate indicating one-half per cent of metallic iron). 

Total iron in a pharmaceutical mixture is determined by boiling the 
liquid or powdered solid material with rrydrochloric acid, adding a little 
nitric acid to oxidize any ferrous salt present, adding ammonium chloride, 
and excess of ammonium hydroxide and boiling until the ferric hydroxide 
separates. The solution is filtered and the precipitate washed with hot 
water, dried, ignited on the filter, and weighed as Fe203. 

If much organic matter is present it may be necessary to pass in hydro- 
gen sulphide after adding the ammonia and precipitate the iron as sulphide. 
The iron sulphide is collected on a filter, washed with water and dissolved 
in hot dilute hydrochloric acid. The clear liquid is boiled with the addi- 
tion of a little nitric acid, ammonium chloride added and the iron pre- 
cipitated with ammonium hydroxide, completing the determination as 
usual. 

Phosphates in solution simultaneously with alkaline earth metals 
complicate the determination. If these substances have been indicated 
by the qualitative tests, the ammonium hydroxide precipitation is con- 
ducted in the usual way, the well-washed precipitated dissolved in dilute 
sulphuric acid, heated, and reduced with metallic zinc. Sufficient sul- 
phuric acid is added to bring all of the zinc into solution, and the iron 
is then titrated immediately with permanganate. 

Most of the pills and tablets which are supposed to contain ferrous 
salts, will contain more or less ferric iron, and an estimation of the total 
iron does not indicate the quantity of the ferrous salt. For quantitative 
purposes the solution of the organic matter with alcohol may result in 
the oxidation of some of the ferrous compound unless the extraction is 
conducted in a closed flask. The estimation of ferrous iron is accom- 
plished in two waj s. 

1. The finely ground substances are boiled with strong alcohol under 
a reflux condenser until the organic matter is dissolved. The super- 
natant liquid is decanted hot, the residue boiled up with a fresh portion of 
alcohol under the reflux, decanted again, and the procedure repeated 
as long as any organic matter dissolves. The flask is then fitted with a 
two-hole stopper containing an outlet tube which can be dipped into a 
beaker of recently boiled water, and an inlet tube, through which passes 
carbon dioxide (or the apparatus described below may be used). The 
substance in the flask is covered with hydrochloric acid, 1.2 sp. gr., pre- 
viously boiled to expel air, a current of carbon dioxide passed into the 



1008 



INORGANIC SECTION 



flask and the mixture boiled. When all traces of alcohol have been driven 
off and the iron salt dissolved, the outlet tube is dipped into the water, 
the carbon dioxide stream checked and about 25 mils of water allowed 
to run back into the flask. The stream of carbon dioxide is allowed to 




flow slowly and the flask rapidly cooled. The stopper is withdrawn and 
the solution poured into a large evaporating dish which contains an acid 
solution of zinc sulphate prepared by dissolving 3 grams zinc in 30 mils 
sulphuric acid 1 in 2, 1000 mils recently boiled and cooled water added, 
and the whole titrated with permanganate. 

If the insoluble material is dark colored and obscures the end reaction, 
the contents of the flask may be transferred to a graduated container 
of any convenient capacity, and made up to volume with recently boiled 




distilled water. After the insoluble material has settled, aliquots are 
pipetted off and titrated. 

2. About 1 gram of the finely powdered substance is weighed into a 
flask and boiled with a small quantity of strong hydrochloric acid diluted 
with about half its volume of water, until the iron salt is dissolved, using 
an apparatus similar to that described above or as follows: 

The solution is transferred to a graduated flask of 100-mils capacity 
and made up to the mark with recently boiled distilled water; 25-mil 



METALS AND THEIR COMPOUNDS 1009 

portions are then titrated with potassium bichromate. The end of the 
reaction is ascertained by means of a freshly prepared dilute solution of 
potassium ferricyanide used as an outside indicator. A number of drops 
of the reagent are placed upon a white plate or tile, and from time to 
time, during the addition of the bichromate, a drop of the solution is with- 
drawn on the end of a glass rod and brought in contact with one of the 
drops of indicator. When the reaction is complete no blue coloration 
is obtained. It is well to carry out a preliminary titration to determine 
approximately the amount of bichromate needed to complete the reaction. 

The total iron in the preparation can be determined in the hydro- 
chloric acid solution by transferring a 25-mil aliquot to a flask, heating 
to boiling and adding a clear freshly prepared solution of stannous chloride 
drop by drop, until the yellow color of the ferric chloride is just discharged. 
Any excess of stannous chloride is removed by adding a few drops of 
mercuric chloride. The iron is then titrated with bichromate. 

Determination of Ferrous Hypophosphite in a Solution of the Salt. — 
The solution as prepared always contains a certain amount of free phos- 
phoric acid. Weigh out the sample into a 250-mil Erlenmeyer flask, 
add 25 mils distilled water, 2 mils concentrated sulphuric acid, and heat 
to boiling. Run in N/10 permanganate gradually, until finally one drop 
produces a fugitive pink color. Then remove one drop of the solution 
on the end of a glass rod, place on a white glazed-porcelain plate and apply 
one drop of a very dilute solution of potassium ferricj^anide. If a blue 
color appears, it shows that the ferrous salt has not been entirely oxidized. 
Continue to add permanganate gradually until on testing one drop with 
the ferricyanide solution there is no blue color obtained. From the 
number of mils of permanganate employed the amount of ferrous hypo- 
phosphite, Fe(PH 2 02)2, is calculated. 

It is well to run a control experiment in the first place with a sample 
equal to that employed in the subsequent determination. 

The iron in organic products is determined b}' igniting the substance 
and dissaving the residue in nitric and hydrochloric acid. The liquid 
is diluted, filtered from any carbonaceous matter, and the iron determined 
as usual. This procedure should be used when working with prepara- 
tions of beef, iron, and wine, and whenever ammonium citrate occurs 
simultaneously with iron. 

Iron Peptonate and Manganese Preparations. — These combinations 
are popular as general tonics and as remedies for chlorosis and anemia. 
The solutions are dark-brown in color, Ferro-Mangan, Dieterich, and 
Pepto-Mangan being representative. The treatment of products of this 
class has been described in detail under Manganese. 

A distinction should be drawn between those compounds in which 
iron is in actual chemical combination with organic substances, and those 



1010 INORGANIC SECTION 

in which it is actually in an inorganic form, but is prevented from respond- 
ing to its characteristic tests, on account of the presence of organic salts 
such as citrates or tartrates. 

ORGANIC IRON PREPARATIONS 

The term, " organic iron " is confined by modern usage to those organic 
compounds of iron which do not give the chemical tests of this metal 
until the structure of the molecule has been destroyed by reagents. 

Ferratin. — Sodium Ferrialbuminate 

Ferratin is the sodium salt of ferrialbiiminic acid, containing iron in 
the ferric state in organic combination, equivalent to 6 per cent metallic 
iron. 

Sodium ferrialbuminate occurs naturally in the organs of mammals, 
especially in the liver. Ferratin is prepared from egg albumin and 
chemically pure iron salts in the presence of alkalies. 

It is a light-brown, tasteless powder, having a faint odor. It is solu- 
ble in weak alkaline aqueous solutions, from which solutions it is pre- 
cipitated by hydrochloric acid. On dissolving .3 gram ferratin in 10 mils 
of water with the aid of a few drops of ammonia water, and then adding 
an equal volume of a 25 per cent potassium carbonate solution, no pre- 
cipitation occurs. 

Hemaboloids 

Hemaboloids is a liquid said to contain in each 100 mils iron com- 
bined with proteins, equivalent to .40 gram elementary iron, proteins and 
nucleoproteins (nitrogen X 6.25) 4.0 grams, bone marrow extract 5.0 
grams, nuclein .04 gram, in a menstruum containing 17 per cent alcohol 
by volume. It is claimed that 75 per cent of the iron is in a stable organic 
combination with vegetable nucleoproteins and does not react with hema- 
toxylin, while the remaining 25 per cent is more loosely combined. 

Ovoferrin 

Ovoferrin is a solution containing 5 per cent of an artificial proteid- 
product in which iron is present in the so-called " organic " or " masked " 
form. 

Ovoferrin is prepared by modifying serum-albumin by electrolysis, 
producing a proteid which is classed by the manufacturers as a vitellin, 
and introducing ferric hydrate into this proteid by heating under pressure. 
The " vitellin " constituent of this preparation should not be confounded 
with the well-known vitellin of yolk of eggs. 



METALS AND THEIR COMPOUNDS 1011 

The solution has a reddish-brown color, little odor, and a flat, slightly 
aromatic and alcoholic taste. 

The solution does not give a blue color on the addition of potassium 
ferrocyanide solution; a blue tint develops slowly if an equal volume of 
5 per cent hydrochloric acid is added to the mixture; a deep-blue color 
develops at once if this mixture is boiled (difference from egg yolk). 

The solution is not precipitated by boiling, but gives precipitates 
with the alkalies, with which it is incompatible. It is also precipitated 
on half saturation with ammonium sulphate. It is not precipitated by 
acids. 

Proferrin 

A compound of iron and milk casein containing iron equivalent to 
about 10 per cent elementary iron and phosphorus equivalent to about 
.5 per cent elementary phosphorus. Prepared by treating an alkaline 
solution of casein with a solution of an iron salt and precipitating with 
acetic acid. It is a brown powder, almost odorless and tasteless, insolu- 
ble in water and dilute acids, slowly soluble in alkalies. If .5 gram is 
shaken with 10 mils distilled water, and the mixture filtered, the filtrate 
should give no precipitate on addition of ammonium hydroxide, and not 
more than a faint bluish tint on addition of a few drops of potassium 
ferrocyanide solution. 

If about 2 grams proferrin is digested for three hours at 40° C, with 
40 mils of .2 per cent hydrochloric acid containing .006 gram pepsin, 
U. S. P., and the resulting mixture filtered, 5 mils of the filtrate diluted 
to 100 mils should produce not more than a faint-blue color on the addition 
of a drop of potassium ferrocyanide solution. 

Triferrin 

Triferrin is ferric paranucleinate; a compound of caseinparanucleinic 
acid with iron, containing 22 per cent of iron, 9 per cent of nitrogen and 
2.5 per cent of phosphorus in neutral (organic) combination. 

It is prepared by digesting cow's milk-casein with pepsin and pre- 
cipitating the solution with a ferric salt. 

It is a tasteless powder, soluble in weak solution of sodium hydroxide, 
but insoluble in weak hydrochloric acid (.1 to .3 per cent). 

Hemogallol 

Hemogallol is an organic iron compound produced from blood by 
reduction of its hemoglobin by means of pyrogallol. 

Fresh defibrinated blood suitably diluted with water is mixed with 
an equal volume of saturated solution of pyrogallol, which causes the pre- 



1012 INORGANIC SECTION 

cipitation of a voluminous precipitate which is separated, washed with 
water to remove pyrogallol, and finally with alcohol. 

It is a reddish-brown, almost tasteless powder, insoluble in water, 
alcohol, etc. 

It does not show the spectroscopic absorption bands of hemoglobin 
between D and E. 

Iron albuminate is a brown powder or scale, soluble in water. Albo- 
ferrin is an iron albumin compound. 

Iron alginate is a brown tasteless powder obtained by precipitating 
a solution of sodium alginate with ferric chloride. It is soluble in ammonia. 

Iron cacodylate is a grayish-yellow powder soluble in water. 

Iron glycerophosphate (ferric) is a yellow powder or scale, soluble 
with difficulty in alcohol and water. 

Ferratogen is a grayish-yellow substance obtained by growing yeast 
in a ferruginous medium. 

Ferrostyptin is a formaldehyde-iron preparation occurring in the form 
of yellow crystals, soluble in water, insoluble in cold alcohol and ether. 

Iron peptonate is prepared by treating an aqueous solution of beef 
peptone with a solution of iron oxychloride and precipitating with ammonia. 
In order to render the iron peptonate soluble in water, the precipitate is 
dissolved in ammonium citrate and the solution condensed to a thick 
jelly or completely dried in vacuo. 

CHROMIUM 

Chromium anhydride, so-called " Chromic Acid " CrCfe, is a caustic 
and astringent. It is used externally in the treatment of running sores 
and ulcers, to check hemmorhage, as an astringent for perspiring feet, 
for leucorrhea, and for foot and mouth disease. 

Potassium bichromate is used in gastric ulcers and syphilis, rand exter- 
nally for treating perspiring feet, tubercular elevations, warts, etc. It is 
combined with antimony sulphide, aconite, belladonna and Bryonia in 
tablets for bronchitis. 

Chromium is estimated by treating a weighed amount of the chromium 
anhydride-containing substance, with sodium hydroxide solution, acidi- 
fying strongly with acetic acid and precipitating hot with lead acetate. 
The lead chromate is then filtered into a tared Gooch, washed with hot 
water containing a little acetic acid, then with alcohol and ether, dried 
and weighed. 

Samples containing potassium bichromate are crushed, leached with 
hot water, filtered, the filtrate treated with sodium acetate and acetic 
acid and precipitated with lead acetate. 

If drug extracts are present, and tannins and soluble gums interfere 



METALS AND THEIR COMPOUNDS 1013 

with a lead precipitate, the whole procedure must be changed. In this 
case the sample is digested with dilute hydrochloric acid, the liquid filtered 
into a beaker, neutralized with sodium hydroxide, acidified with hydro- 
chloric acid and subjected to the action of hydrogen sulphide until the 
color of the chromate has disappeared. The container is allowed to stand 
in a moderately warm place until the sulphur has settled, filtered into a 
porcelain or platinum dish and washed, the filtrate boiled to expel any 
residual hydrogen sulphide, cooled, ammonia added in slight excess, and 
the mixture exposed to a temperature approaching boiling until the liquid 
over the precipitate is perfectly colorless. The liquid is then decanted 
through a filter, the precipitate washed three times by decantation with 
hot water, finally brought onto the filter, washed, dried and ignited. The 
residue is O2O3, 

ALUMINUM 

Aluminum silicate is a component of antiphlogistic pastes which have 
attained considerable reputation. It provides the base, and is combined 
with glycerin, boric acid, menthol, thymol, eucalyptol, and ammonium 
iodide. 

The double sulphate of potassium and aluminum (Alum) is a power- 
ful astringent, used internally in painter's colic, in uterine injections and 
washes, and in styptic pencils. Uterine astringents and washes contain 
alum, zinc sulphate, morphin and Hydrastis, tannin and boric acid; and 
alum, boric acid, tannin, thymol, eucalyptol, salicylic acid, Helonias, 
Hyoscyamus, opium, and Hamamelis. Aluminum and ammonium sul- 
phate (ammonia alum) is used for similar purposes. 

Aluminum hydrate is employed in diarrhea and dyspepsia. It is 
sometimes combined with metallic aluminum and calcium carbonate. 
Aluminum acetate and chloride are used as disinfectants. Aluminum 
sulphocarbolate (Sozol) and aluminum naphthol-disulphonate (Alumnol) 
are used as substitutes for iodoform. They are both soluble in water 
and a solution of the latter fluoresces blue. 

To determine aluminum, five to ten tablets are ground or 10 to 25 mils 
of a solution evaporated to dryness, and ignited, if much organic matter 
is present, until the mass is completely charred. The residue is extracted 
with warm hydrochloric acid 1-1, fTtered into a beaker, made up to 150 
mils, 25 mils ammonium chloride solution added and brought to a boil. 
Dilute ammonia is added in slight excess, the solution boiled for one minute, 
the precipitate allowed to settle, washed by decantation, filtering through 
a filter with a cotton plug. The precipitate is washed with 10 per cent 
ammonium nitrate solution and then burned wet, ignited to constant 
weight over a blast lamp and weighed as AI2O3. 



1014 INORGANIC SECTION 

If zinc or calcium are present they can of course be determined in the 
filtrate. 

Phosphates and iron complicate this determination. The former are 
usually present in small quantity, if the tablets contain much drug extrac- 
tive, and iron often occurs as an impurity. If iron is present in quantity, 
the ignited residue should be dissolved in aqua regia, the acid evaporated, 
the residue dissolved in hydrochloric acid 1 to 1, the iron reduced by adding 
zinc and titrated with permanganate after pouring the solution into a 
solution of 3 grams of zinc dissolved in 30 mils sulphuric acid 1 to 2, and 
1000 mils of recently boiled distilled water. 

Phosphoric acid can be estimated by dissolving the precipitate in 
aqua regia, evaporating, dissolving in dilute nitric acid, precipitating with 
ammonium molybdate and completing the determination as usual. 

MANGANESE 

Manganese does not functionate to a great extent in medicinal prod- 
ucts, but it will be overlooked many times unless the analyst is watch- 
ful. It is used principally in tonic mixtures, both liquid and pill, where 
it accompanies iron, and it will be found in the metallic hypophosphite 
preparations, and in the organic tonics of the Pepto-mangan type. Man- 
ganese iodide, lactophosphate, carbonate, and citrate have a limited use, 
but the principal form in which manganese is dispensed is the dioxide. 

The well known " pink pill " formulas consist of manganese dioxide, 
ferrous carbonate, gentian, strychnin, and licorice. Manganese iodide is 
combined with Leptandra, Juglans, Sanguinaria, and Hyoscyamus. Man- 
ganese dioxide has been reputed as an emmenagogue and should be looked 
for in emmenagogue pills. 

Determination of Manganese. — Twenty-five mils of a liquid prepa- 
ration is evaporated to dryness and gently charred, or ten to twenty pills 
are ground and charred. Fifteen mils of concentrated nitric acid are 
added to the residue, evaporated to dryness on the steam-bath, the car- 
bonaceous matter burned at a low heat, the addition of a further quantity 
of acid and repetition of the evaporation being carried out if necessary. 
After cooling, 10 mils of concentrated hydrochloric acid are added, and 
the dish covered and heated on the steam-bath until the iron has gone 
into solution. The acid is then evaporated to dryness, a further quantity 
added and evaporated to a syrupy consistency. One hundred mils of 
cold water are added, the solution filtered into a large beaker, thoroughly 
washing any precipitate left on the filter. The filtrate which should 
amount to about 200 mils, is treated with a strong solution of sodium 
carbonate until the precipitate formed dissolves but slowly. The car- 
bonate is then added carefully 2 to 3 mils at a time, with vigorous stirring, 
allowing several minutes to elapse between each addition to determine 



METALS AND THEIR COMPOUNDS 1015 

whether the precipitate dissolves or not. When a decided precipitate 
remains, 2 drops of hydrochloric acid are added, well stirred, and the 
solution allowed to stand for several minutes. If it does not clear, a further 

2 drops of acid are added, and this operation continued, until sufficient 
has been added to just dissolve the precipitate. Two grams of sodium 
acetate are dissolved in a little hot water and added to the solution, followed 
by 500 mils of boiling water, the beaker heated to boiling, and allowed to 
stand for ten minutes at the boiling temperature; the lamp is then removed 
and the precipitate allowed to settle. The supernatant liquid is decanted 
through a filter containing a plug of cotton, the precipitate brought onto 
the filter and washed with boiling water, the filtrate and washings trans- 
ferred to a porcelain evaporating dish and evaporated rapidly. When 
the precipitate has thoroughly drained, the filter containing it is trans- 
ferred to the beaker in which the precipitation was made, the iron dis- 
solved in 10 mils concentrated hydrochloric acid and a little water, filtered 
into a liter beaker, washing as usual and repeating the precipitation and 
filtration precisely as in the first case, adding the filtrate to the first one. 
The evaporation is continued until about 300 mils remain and the liquid 
filtered into a 500-mil beaker. Ten grams of sodium acetate are added, 

3 to 5 drops of acetic acid and then ammonia until the liquid is decidedly 
alkaline. A few mils of bromin are added, the solution stirred, heated 
to boiling for five minutes, occasionally adding a little bromin water. 
The precipitate is allowed to settle, filtered, washed with hot water, dried 
and ignited to constant weight over a blast lamp. The ignited substance 
is Mn30 4 . 

Volumetric Method for Determining Manganese. — The sample is pre- 
pared in the same way as described above, treated with 15 mils of nitric 
acid, sp. gr. 1.2, and boiled until nitrous fumes ceased to be given off. 
One gram of red lead is added, 30 mils of hot water and the mixture boiled 
four to five minutes. The supernatant liquid is decanted into a beaker 
and the residue boiled with hot water containing 20 to 25 per cent of 
nitric acid. The boilings and decantations are continued as long as they 
show a decided color, and the united decantations are filtered through 
asbestos which has been ignited in oxygen gas. The filtered solution is 
then made up to a definite volume and aliquots titrated with sodium 
arsenite solution. 

The reagent is prepared and standardized as follows: .495 gram of 
sodium arsenite is dissolved in 300 mils water containing 2.5 gram sodium 
carbonate and diluted to 1 liter. It is run against N/100 permanganate 
by transferring a measured quantity of the latter to a flask, adding 50 
mils water and 20 to 30 mils nitric acid 1.2 sp. gr. free from nitrous fumes, 
and titrating cold. 

2Mn 2 07+5As 2 03 = 4MnO+5As 2 5 



1016 INORGANIC SECTION 



PERMANGANATES 



Potassium permanganate is used as an antidote in poisoning by alka- 
loidal salts, as an antiseptic for wounds and running sores, as an injection 
in leucorrhea, etc., and to a limited extent in mouth washes. Zinc per- 
manganate is also used as an antiseptic. 

Solutions of permanganates are usually made up directly from the 
salt or from compressed tablets. 

The percentage of actual permanganate in the salt or tablet is deter- 
mined by dissolving a small quantity of the substance (.1 to .5 gram) in 
water, acidulating with 5 mils dilute sulphuric acid, warming to 60° C. 
and titrating with N/10 oxalic acid. 

One mil N/10 oxalic acid = .0040842 gram Zn(Mn0 4 ) 2 +6H 2 0. 

ZINC 

Zinc salts are employed as tonics and astringents. The oxide will be 
found in toilet and face powders combined with talc, and as an exsiccant 
to inflamed and excoriated surfaces. It is combined with quinin, strychnin, 
Capsicum, and arsenous acid in pills used for dipsomania; with anti- 
pyrin, belladonna and Castanea for whooping cough; with Hydrastin, 
belladonna, salicin, and pepsin for night sweats. Zinc bromide is employed 
in epilepsy and other spasmodic affections, combined with atropin, ergotin, 
lupulin, and Scutellaria. Zinc acetate will be found in astringent washes 
with lead acetate, berberin, and morphin. Zinc chloride is present in 
mouth washes and pyorrhea remedies, combined with betanaphthol, men- 
thol, and formaldehyde. Zinc sulphate is combined with phosphorus, 
lupulin, and Valeriana; with alum, morphin, and Hydrastis; with lead 
acetate, morphin, and hydrastin; with alum, boric acid, tannin, morphin, 
and Hydrastis. Zinc phosphide is present in aphrodisiac pills which 
contain the salt by itself, and in combination with one or more of the 
following: Nux Vomica, reduced iron, Cannabis sativa, Hyoscyamus 
and Damiana. Zinc valerianate is combined with phosphorus and mor- 
phin; with phosphorus and strychnin; with the valerianates of iron, 
sometimes with addition of sumbul, and gold, and sodium chloride; with 
iron ferrocyanide, quinin, and Valeriana. Zinc sulphocarbolate is employed 
as an antiseptic wash and gargle, and internally as an intestinal anti- 
septic, where it is often combined with aloin; with bismuth salicylate; 
with the sulphocarbolates of calcium and sodium; and with salol, bismuth 
subnitrate, calomel, and pancreatin (cholera infantum tablets) . Zinc per- 
manganate is used as an astringent and antiseptic in urethritis. Zinc 
stearate is often used as a substitute for the oxide in dusting powders 
combined with acetanilid, and as an astringent in gonorrhea. 






METALS AND THEIR COMPOUNDS 1017 

Determination of Zinc. — Zinc can usually be determined in simple 
mixtures by dissolving out the zinc salt with hydrochloric acid, precipi- 
tating with sodium carbonate, and igniting the zinc carbonate to con- 
stant weight. In most medicinal preparations and in talcum powders, 
even when iron is absent as an essential ingredient, small quantities of 
this element occur as an impurity, hence it is a good rule to get rid of the 
iron and other substances which may be thrown out by ammonia in the 
presence of ammonium chloride, and then precipitate the zinc as 
sulphide (in the presence of acetic acid if manganese is present), niter 
off the sulphide, dissolve it in hydrochloric acid, and precipitate as 
carbonate. 

In the case of a powder .2 to .5 gram are used as a sample; of a tablet 
from 10 to 20; and of a liquid 10 to 25 mils are evaporated to dryness; if 
starch is present, the material is extracted with strong hydrochloric acid 
in the cold, but if absent it may be boiled with a moderately diluted acid, 
filtering into a beaker and washing thoroughly. If bismuth is present 
the acid solution is precipitated by hydrogen sulphide, the bismuth sul- 
phide filtered off, the filtrate boiled to expel the excess of hydrogen sul- 
phide, a few drops of nitric acid added to oxidize the iron, and the solution 
cooled, some ammonium chloride added, excess of ammonia and boiled 
until the iron is fully precipitated. After filtering off the iron, the warm 
filtrate in a flask is subjected to the action of hydrogen sulphide (if man- 
ganese is present excess of acetic acid must be added) until the zinc is 
completely precipitated, the flask is filled up to the neck with hydrogen 
sulphide water and set aside in a warm place for twelve to twenty-four 
hours. The zinc sulphide is collected on a filter and washed with hot 
water. The filter containing the zinc sulphide is transferred to a beaker, 
covered with an excess of hydrochloric acid 1 to 1, warmed until the hydro- 
gen sulphide is driven off, filtered into a capacious porcelain casserole, 
washing with hot water. The solution is heated nearly to boiling and 
sodium carbonate added drop by drop until the liquid has a strong alkaline 
reaction, boiled a few minutes, the precipitate allowed to subside, the 
supernatant liquid decanted through an ashless filter, the precipitate 
washed three times by decantation with hot water, finally transferred 
to the filter, washed with hot water, and dried. The dry zinc carbonate 
is then tapped into a porcelain crucible and ignited to constant weight. 
The filter is burned in a platinum cage and the ash dropped into a crucible, 
treated with a few drops of nitric acid, the acid evaporated and the residue 
ignited at a low red heat. The product is zinc oxide, ZnO, and represents 
the total zinc present in the product. 

When working with preparations containing zinc permanganate, the 
permanganate should be reduced by boiling the solution with alcohol 
before proceeding with the analysis. Practically all of the manganese 



1018 INORGANIC SECTION 

will separate as oxide, but the manipulation should follow the directions 
given above for precipitating the zinc in presence of manganese. 

CERIUM 

Cerium oxalate, Ce2(C204)3*9H20, is employed in many forms of 
gastric disturbances. It is dispensed in pills and tablets either alone or 
in combination with bismuth subnitrate; with Nux Vomica, pepsin, creo- 
sote and cocain. The commercial salt is really a mixture of the oxalates 
of the so-called rare earths, the cerium predominating. 

On ignition, it is converted to cerium oxide, Ce02, which is permanent, 
and oxides of accompanying bases, and can be used as a means of estima- 
tion. It amounts to about 47 per cent of the weight of the oxalate. 
Cerium oxide, obtained by igniting the salt, when dissolved in concen- 
trated sulphuric acid is the cause of the development of a blue color chang- 
ing to purple and red on adding strychnin, and this test is of value in detect- 
ing the presence of cerium oxalate in admixtures. 

Cerium oxalate can be separated from bismuth subnitrate by boiling 
the sample with dilute hydrochloric acid in which both dissolve, and pre- 
cipitating the bismuth with hydrogen sulphide. The cerium can then 
be thrown out as hydroxide by adding excess of potassium hydroxide and 
boiling. The hydroxide is filtered off, washed with hot water, dried, and 
ignited. 

If cerium oxalate occurs in a preparation which contains no other 
metallic salts, it can be determined by direct ignition of the sample and 
weighing the oxide. 

STRONTIUM 

Strontium salts have a limited use in medicine. The bromide, iodide, 
and salicylate are recognized in the Pharmacopoeia. The peroxide is 
used in ointments and dusting powders. 

Strontium is determined, if in the form of a soluble salt, by direct pre- 
cipitation of a solution with ammonium carbonate in the presence of 
ammonia. If the salt is insoluble in water it is brought into solution with 
a minimum quantity of hydrochloric acid and precipitated as above. The 
container is allowed to stand for several hours in a warm place, filtered 
onto an ignited tared Gooch, washed with water containing a little 
ammonia, dried, and ignited at a low heat. . Strontium carbonate, SrC03, 
loses its CO2 gradually at an intense heat. 

If phosphates are present they must be removed before precipitating 
with ammonium carbonate. If ammonia in presence of ammonium chloride 
produces a precipitate, and this precipitate, is found to consist in part 
of phosphates, sufficient hydrochloric acid is added to dissolve the pre- 



METALS AND THEIR COMPOUNDS 1019 

cipitate, and the solution is made nearly neutral by the addition of sodium 
carbonate. A mixture of sodium acetate 10 per cent and acetic acid is 
added and the solution boiled and filtered if necessary. Ferric chloride 
is added to the filtrate drop by drop until precipitation is complete, at 
which point the liquid will begin to assume a distinct reddish color, and 
the mixture gently boiled for a few minutes (whereby the ferric acetate 
is converted into insoluble basic acetate) and then filtered. The solu- 
tion now contains any zinc or manganese and the alkaline earths as chlor- 
ides and their separation and determination can follow the usual methods. 
If calcium occurs simultaneously with strontium, the latter may be 
separated by treating the ammoniacal solution with about fifty times 
the quantity of the substances as weighed, of ammonium sulphate, and 
either boiling for some time with renewal of the water that evaporates, 
adding sufficient ammonia to keep the solution faintly alkaline, or allow- 
ing the determination to stand at the ordinary temperature for twelve 
hours. The precipitate which consists of strontium sulphate and a little 
ammonium strontium sulphate, is filtered, washed with a concentrated 
solution of ammonium sulphate, till the washings remain clear on the 
addition of ammonium oxalate, cautiously ignited, moistened with a little 
dilute sulphuric acid, reignited, and weighed. The diluted filtrate is then 
precipitated with ammonium oxalate for the determination of calcium. 

CALCIUM 

Calcium salts are used in medicinal preparations both for therapeutic 
and mechanical effects. Calcium carbonate and sometimes the phos- 
phate are present in tooth powders, pastes, and face powders, and the 
same salts, and also calcium sulphate, will often appear in pills and tablets 
as diluents and coating material. 

Calcium peroxide is being used to some extent in tooth powders. 
Calcium sulphide and iodide are extensively employed. Calcium car- 
bonate and phosphate occur in saline and chalybeate tonic mixtures 
combined with the chlorides and carbonates of sodium and potassium, 
magnesium carbonate, reduced iron and ferrous carbonate mass. Anti- 
acid mixtures include calcium carbonate with magnesium carbonate and 
sodium chloride. 

Calcium hypophosphite is extensively employed in pill, tablet, and 
syrup form combined with the hypophosphites of sodium, potassium, 
manganese, iron, quinin, and strychnin, sometimes with guaiacol or creo- 
sote. Calcium hypophosphite will be found in tonic emulsions of cod- 
liver oil, and with petrolatum. 

Calcium phosphate occurs in the saline and chalybeate mixtures 
described above and in pills and syrups with the phosphates of potassium, 
magnesium, iron, quinin and strychnin and phosphoric acid. 



1020 INORGANIC SECTION 

Calcium lactophosphate occurs in pills and syrups with the digestive 
ferments, and with the lactophosphates of iron, manganese, potassium, 
and sodium. 

Calcium bromide is a remedy for epilepsy and hysteria, and is combined 
with the bromides of the alkali metals and ammonia. 

Calcium glycerophosphate functionates as a nerve and general tonic, 
and is often found with alkali glycerophosphates and soluble casein. 

In order to estimate calcium, consideration must be taken of the pres- 
ence of any phosphates or heavy metals of the third group in the prepa- 
ration under examination. If phosphates are present, they must be removed 
by dissolving the sample in dilute hydrochloric acid and proceeding as 
described for the separation of phosphates under the discussion of stron- 
tium. Any zinc or manganese can then be removed from the filtrate by 
adding ammonium chloride, rendering ammoniacal, and precipitating 
with hydrogen sulphide. The filtrate and washings from this treatment 
are boiled ' until free of hydrogen sulphide. The ammonium chloride 
already added should be in sufficient amount to hold up any magnesium 
(if this be present) from being precipitated by ammonia. The process 
takes the following course depending on the presence or absence of mag- 
nesium. 

1. If Magnesium is Absent. — Ammonia is added until the liquid has 
a decided odor of the reagent and the liquid is heated to boiling. A warm 
strong solution of ammonium oxalate, to which a little ammonia has been 
added, is introduced in slight excess, the mixture boiled for a few minutes 
and allowed to settle. The clear liquid is then decanted through a well- 
matted Gooch, without disturbing the precipitate. The latter is washed 
three or four times by decantation with boiling water, allowing it to settle 
completely each time. The precipitate is then brought onto the filter 
and washed with warm water until the filtrate is free from ammonium 
oxalate. A flask is then inserted under the stem of the Gooch, the pre- 
cipitate dissolved in a small quantity of warm hydrochloric acid, and the 
Gooch well washed with warm water. The solution is treated with a few 
mils of concentrated sulphuric acid, diluted to 250 mils with water, heated 
to 60 to 70° and the oxalic acid titrated with N/10 permanganate; 63 
parts of oxalic acid are equivalent to 70 parts of calcium, or 1 mil N/10 
KMn04 = .002 gram calcium. 

2. If Magnesium is Present. — Ammonia is added in slight excess, 
followed by ammonium oxalate as long as a precipitate forms, then a 
further portion of the same reagent, about sufficient to convert the mag- 
nesium to oxalate (which remains in solution). The mixture is allowed 
to stand at the ordinary temperature for twelve hours, the supernatant 
liquid decanted as completely as possible, the precipitate washed once 
by decantation and the filtrate and washings set to one side, and the pre- 



METALS AND THEIR COMPOUNDS 1021 

cipitate dissolved in hydrochloric acid, diluted with water, made ammonia- 
cal and precipitated with ammonium oxalate, the mixture allowed to stand 
as before, washed by decantation onto the filter previously used, and the 
washings continued until free of ammonium oxalate. The precipitate is 
then dissolved in HC1, H2SO4 added and titrated as above described. 
The first filtrate contains most of the magnesium, the second portion, 
acidified with hydrochloric acid, is evaporated to small volume and then 
added to the first portion. The clear solution is then treated with an 
excess of sodium phosphate and the mixture stirred, care being taken to 
avoid touching the sides of the beaker with the stirring rod. The beaker 
is then covered, allowed to stand twelve hours without warming. The 
precipitate is collected on an ashless filter, any particles adhering to the 
beaker being scraped off with a piece of filter paper, washed with a mix- 
ture of 3 parts water and 1 part ammonia, sp. g. .96, until free from chlor- 
ides. The filter and precipitate are dried and then ignited in a platinum 
crucible. If the magnesium pyrophosphate is dark, the crucible is cooled, 
the salt moistened with nitric acid, the excess of acid evaporated and 
reignited. 

Determination of Calcium in Presence of Phosphate and Absence of 
all Other Metallic Phosphates Except the Alkalies. — The sample is dis- 
solved in dilute hydrochloric acid, ammonia added until a precipitate 
begins to form, the precipitate dissolved by the addition of a drop of 
hydrochloric acid, ammonium oxalate is added in excess and finally 
sodium acetate, the treatment of the precipitated oxalate and remainder 
of the determination following the procedure directed in 1 above. 

MAGNESIUM 

Magnesium salts are used as laxatives, refrigerants, antiacids, and 
diuretics. Magnesium oxide (calcined magnesia) is used in certain forms 
of dyspepsia, sick headache, acid conditions of the stomach, etc. ; it is com- 
bined with rhubarb in tablets, and with charcoal, ginger and pepsin in 
lozenges. It often accompanies cascara extracts in pills, tablets, and 
capsules. Magnesium acetate is combined with rhubarb. Magnesium 
carbonate is combined with calcium carbonate and sodium chloride; and 
with the chlorides, sulphates, and carbonates of sodium and potassium, 
carbonate and phosphate of calcium, reduced iron and ferrous carbonate 
in saline and chalybeate tonic compounds. Magnesium phosphate is 
combined with the phosphates of potassium, calcium, iron, quinin, and 
strychnin, and phosphoric acid in tablets and syrups. 

Magnesium sulphate is combined with ferrous sulphate, quassia, and 
sulphuric acid. This salt is a component of many of the so-called efferves- 
cent citrate of magnesia preparations. Many of these products contain 



1022 INORGANIC SECTION 

magnesium sulphate in an effervescent base of citric and tartaric acids, 
and sodium bicarbonate often with the addition of sodium and potassium 
tartrate. Magnesium citrate, the true salt, is used in effervescent com- 
bination. 

Magnesium oxide is sometimes used as an absorbant material for 
castor oil when it is desired to adminster the latter substance in a dis- 
guised form. 

The determination of magnesium when it occurs alone or in com- 
bination with the alkali metals, is effected by bringing the substance into 
solution with water or dilute hydrochloric acid if necessary, adding ammo- 
nium chloride followed by ammonia, which should produce no precipitate. 
Sodium phosphate is then added drop by drop with constant stirring until 
a considerable excess is present, a further quantity of ammonia added, 
the beaker covered and set aside for several hours. The liquid is filtered 
and the precipitate washed with dilute ammonia (3 to 1) until free from 
chloride, dried and ignited as Mg2P207. 

When phosphates are present or the mixture contains alkaline earth 
metals, the determination follows the directions given under calcium on 
page 1020. 

Mixtures containing sugar, plant extractive, or organic matter should 
be incinerated before attempting to separate the magnesium. The ash 
is dissolved in hydrochloric acid and the estimation continued as usual. 
If phosphates are present in considerable quantity it will be impossible 
to obtain a white ash, and extreme temperatures should be avoided. As 
soon as the char is obtained, the dish is cooled, the mass extracted with 
dilute hydrochloric acid, and the liquid filtered off, washing free from 
acid with distilled water. The filter and carbonaceous matter is then 
reignited, if necessary with the addition of a small quantity of ammonium 
nitrate. 

THE ALKALI METALS AND AMMONIUM 
Sodium 

Sodium salts will be encountered in a great variety of medicinal prepa- 
rations. The bicarbonate usually accompanies calomel, and is often 
combined with acetanilid, caffein, and the bromides in headache powders 
and tablets. It is one of the ingredients of soda mint tablets, lithia tab- 
lets, and in a partly converted form, furnishes the effervescing feature of 
the granular effervescent salts. 

Sodium bromide is an ingredient of a large number of headache mix- 
tures sold in the form of powders, tablets, and liquids. 

Sodium chloride is a component of nasal tablets and liquid prepara- 



METALS AND THEIR COMPOUNDS 1023 

tions used as douches, where it is often combined with borax and other 
sodium salts. 

Sodium hypophosphite is sold for its tonic value, and occurs with other 
metallic hypophosphites, quinin, and cod-liver oil emulsions. The glycero- 
phosphate is used for .the same purpose. 

Sodiuin phosphate is an ingredient of inorganic laxative preparations 
" liver salts," and effervescent salts. 

Sodium salicylate is used in antirheumatic remedies, often in combina- 
tion with other alkali salicylates, and in migraine tablets with antipyretics, 
camphor monobromated, Hyoscyamus and Gelsemium. 

Sodium sulphocarbolate is used as an intestinal antiseptic. 

Sodium sulphite is an antiferment, and will occasionally be found in 
special combinations intended for certain forms of indigestion. 

More than one sodium salt is often present in a single preparation. 
The other alkalies are used simultaneously in many instances, and the 
analyst may be at a loss to determine the proper acid radicle to which 
to attribute the metal. Often his only conclusion can be that the prepa- 
ation contains the chlorides, sulphates, and phosphates of sodium, potas- 
sium, and hthium. If the importance of the analysis warrants, the quan- 
tities of the different radicles can be determined and the proper equilibrium 
determined by a study of the figures. 

If sodium occurs as the only alkali metal, the quantity of the combi- 
nation present is probably best figured from the determination of the acid 
radicle. 

Sodium Bicarbonate 

This salt when free from normal carbonate, gives no color with phenol- 
phthalein, but does react alkaline to methyl red and methyl orange, and 
can be titrated with acid against these indicators. The determination 
of sodium bicarbonate in admixture with acetanilid and other substances 
of like nature has been fully described in the section dealing with those 
bodies. 

POTASSIUM 

Potassium salts enter into the composition of remedies intended for 
a great variety of aihnents. 

Several of the potassium salts, such as the acetate, bicarbonate, bitar- 
trate, carbonate, and nitrate are reputed to possess diuretic properties, 
and one or the other usually is present in the common kidney pills and 
liquid mixtures for kidney diseases. Kidney pills also contain extract 
of buchu, juniper berries, Digitalis and Squill as therapeutic agents. 
Methylene blue is occasionally added, not only for its remedial value, but 



1024 INORGANIC SECTION 

for the sensational effect on the consumer, who is led to believe by the 
advertising matter that the peculiar color imparted to the urine is an 
indication that the remedy is producing the desired effect. Potassium 
nitrate is present in liquid remedies. Potassium bicarbonate is used in 
pills for the relief of cystitis, and may be combined with boric acid, atropin, 
and the extracts of buchu, triticum, Hydrangea, cornsilk, and Viburnum 
prunifolium. It is also present in liquid remedies for stomach troubles 
with rhubarb, Hydrastis, and digestives. 

Potassium bichromate is a component of bronchitis pills and tablets, 
with aconite, belladonna, Bryonia, * and sulphurated antimony. It is 
used as a remedy for gastric ulcer. 

Potassium bitartrate, combined with sulphur, is a common house- 
hold remedy. 

Potassium bromide is used in sedative mixtures for nervous condi- 
tions. It is often combined with other bromides, with Hyoscyamus, 
Cannabis sativa, chloral, Grindelia, and Eriodictyon. Granular efferves- 
cent caffein and potassium bromide is a well-known preparation. 

Potassium carbonate and ferrous sulphate furnish the well-known 
Blaud pills. Potassium carbonate is dispensed with aloes, and with 
rhubarb and Hydrastis. It is one of the ingredients of saline and chaly- 
beate tonics, with carbonates of sodium, calcium, and magnesium, potas- 
sium sulphate, sodium and potassium chloride, calcium phosphate, reduced 
iron, and Vallet's mass. 

Potassium chlorate is a household remedy for sore throat and is found 
by itself and combined with ammonium chloride, borax, and cocain. 

Potassium hypophosphite is combined with other hypophosphites in 
tonics and remedies for nervous troubles both liquid and solid. 
w Potassium iodide is employed as a remedy for asthma, syphilis, scrof- 

Jf ula, dropsy, and rheumatism. Asthma mixtures will contain potassium 
iodide, bromides, arsenites, Lobelia, Euphorbia pilulifera, belladonna, 
opium. In syphilitic preparations mercuric chloride, arsenic, and ferrous 
iodides, opium and Nux Vomica may accompany potassium iodide. Rheu- 
matic formulas will include colchicin, digitalin, guaiac, Phytolacca, sali- 
cylic acid, Gelsemium, and Cimicifuga. The well-known " Sarsaparilla " 
and blood remedy type of preparations may contain potassium iodide, 
sarsaparilla, Phytolacca, Stillingia, triticum, Trifolium, Arctium lappa, 
Berberis aquifolium, Xanthoxylum, Bicucculla canadensis and Cascara 
amagra. 

Potassium nitrate is combined with extract of white pine bark, wild 
cherry, squill, senega, ipecac, Sanguinaria, opium and methyl salicylate 
in white-pine compound tablets. It is combined with Aconite, opium, 
and camphor in cold tablets. 

Potassium osmate is used to relieve night sweats of phthisis. 



METALS AND THEIR COMPOUNDS 1025 

Potassium phosphate is used as an alterative and is combined with 
other phosphates in tablets and elixirs. 

Potassium and sodium tartrate (Rochelle salt) is the laxative ingredient 
of Seidlitz mixture. It is often combined with magnesium sulphate in 
granular effervescent salts, and in aperient pills and elixirs it functionates 
with senna, cascara, colocynth, aloes, Leptandra, and juglans. 

Potassium sulphate will be found in nasal tablets, saline and chaly- 
beate tonics, and in purgative mixtures. 

LITHIUM 

Lithium salts are used as diuretics and antirheumatics. The benzoate 
is combined with potassium bicarbonate and the chloride, phosphate, 
and bicarbonate of sodium; also with the salicylate and Hydrangea 
(Lithiated Hydrangea) . 

Lithium carbonate and benzoate are the Uthium salts present in 
" Lithia tablets," the other ingredients being citric acid, potassium bicar- 
bonate, and boric acid. 

Lithium carbonate is sometimes combined with sodium arsenate, and 
with nickel bromide, codein sulphate, ipecac, and oil of anise. 

Lithium citrate is usually produced by the action of citric acid on 
lithium carbonate, and the salt as an individual is seldom dispensed. 
Granular effervescent preparations of Hthium citrate contain lithium car- 
bonate in an effervescent base of citric or tartaric acid, sodium or potas- 
sium bicarbonate, sodium phosphate, magnesium sulphate and caffein, 
strontium and ammonium salicjdates are often included. 

Lithium salicylate is combined with other alkali salicylates, manaca, 
coichicin, Phytolacca, and Cimicifuga. 

Lithium bromide occurs with other bromides in some of the proprietary 
remedies for epilepsy and nervous affections. 

AMMONIUM 

Ammonia water is used as an ingredient of liniments, and the free 
gas is readily detected by holding a piece of moistened red litmus over 
the mouth of the bottle. Ammonia and ammonium carbonate are the 
essential ingredients of smelling salts. 

The compound of ammonium which is most extensively used in medi- 
cine is the chloride. In cough lozenges it is dispensed alone and in com- 
bination with potassium chlorate; with cubeb, licorice, and codein; in 
bronchial mixtures with licorice, Tolu, cubeb, Hyoscyamus, senega, and 
ipecac; with licorice, opium, benzoic acid, camphor, tartar emetic, and 
oil of anise (brown mixture); with cocain, cubeb, and licorice; with 
quinin, camphor, opium, belladonna, and aconite (Coryza); with tartar 



1026 INORGANIC SECTION 

emetic, Sanguinaria, and morphin. Many liquid combinations recom- 
mended for coughs and bronchial troubles contain ammonium chloride, 
licorice, aromatic balsams, opium alkaloids, senega, and ipecac. 

Ammonium bromide has a limited use, and may be expected in the 
same class of combinations which contain the bromides of the alkali 
metals. 

Ammonium carbonate is employed as a cardiac stimulant in fevers, 
pneumonia, and bronchitis. It is combined with asafetida and opium; 
with squill, senega, and opium; and with ammonium bromide, squill, 
aconite, senega, grindelia, and guaiac. 

Ammonium salicylate will be found in rheumatism and headache 
mixtures, and ammonium valerianate is used in nervous and spasmodic 
disorders. 

ESTIMATION OF THE ALKALI METALS 

General Observations. — If the sample under consideration consists 
of a single alkali salt of an inorganic acid, the acid radicle may be deter- 
mined, and the quantity of the metal calculated therefrom. 

When the determination of the metals themselves is essential the 
following points should be observed : 

If the specimen consists of a nitrate or salt of an organic acid, it should 
be converted to sulphate by adding free sulphuric acid 1 to 1, evaporating 
and igniting. 

If the sample consists of a complex mixture of drug extractive, with 
salts of the alkali metals, and perhaps other metallic salts, the organic 
matter should be destroyed completely by one of the following methods: 
careful ignition; boiling with aqua regia; digestion with concentrated 
sulphuric acid in a Kjeldahl combustion flask; combustion with sulphuric 
and nitric acids. If the sample is to be charred, do not carry the com- 
bustion to a complete carbon-free ash. Heat until it is well carbonized, 
then cool, extract with hot dilute acid, filter, wash, reignite the filter and 
residual carbon, extract with acid, and repeat if necessary. 

If the sample contains no organic matter, nitrates, salts of organic 
acids, direct solution in water or dilute hydrochloric acid will usually suffice 
to get the desired elements in shape for subsequent manipulation. 

From this point, however the solution was effected, the analysis pro- 
ceeds in a systematic way, removing any heavy metals by the use of 
hydrogen sulphide, filtering and eliminating the alkaline earth metals 
by appropriate means. The solution is made up to some definite volume 
100-250 c.c. and aliquots taken for the assay. 

In presence of phosphates (unless the only salt present is an alkali 
phosphate) acidulate with hydrochloric acid, add an excess of ferric 






METALS AND THEIR COMPOUNDS 1027 

chloride followed by sufficient ammonia to neutralize the greater portion 
of the free acid, mix with ammonium acetate in not too large excess and 
boil. Filter from the precipitated ferric phosphate at boiling temperature 
and wash with boiling water containing ammonium acetate. The filtrate 
will then contain the alkali metal free from phosphate. 

Boric acid may be removed by mixing in a platinum dish the dry salt 
or a dry residue obtained by evaporating a liquid product with sufficient 
hydrofluoric acid (which leaves no residue on evaporation in a platinum 
dish), digesting, then adding concentrated sulphuric acid drop by drop, 
heating gently at first and then more strongly until the excess of sulphuric 
acid is completely expelled. The boric acid is expelled as fluoride of boron, 
BF3, and the residue contains the metals in the form of sulphates. 

Removal of Alkaline Earth Metals. — The solution rendered slightly 
acid with hydrochloric acid, is brought to boiling, a slight excess of ammo- 
nium hydroxide added, followed by ammonium carbonate and ammonium 
oxalate. After cooling the solution is filtered and the precipitate washed. 

Ammonium chloride, if present, tends to hold magnesium in solution. 
If magnesium is present and it has been necessary to remove heavy metals, 
and ammonium chloride has been formed or added, the solution should 
first be evaporated to dryness, and the residue ignited below a red heat 
until ammonium salts have been driven off. After cooling it is dissolved 
in water and the analysis continued according to the regular program. 

ESTIMATION OF POTASSIUM, SODIUM AND LITHIUM 

The solution of one or more of the alkali metals, freed from other 
metals as above described, is rendered slightly acid with hydrochloric 
acid and concentrated in a porcelain or platinum dish (in the case of 
bromides or iodides the use of platinum must be avoided). Sufficient 
sulphuric acid (1 to 1) to convert all of the metal to normal sulphate is 
added, the evaporation continued until no further diminution in volume 
occurs. The residue is then ignited, using great caution in the early 
stages of the process to prevent loss by decrepitation. The final product 
is the normal sulphate of the metal, and is to be weighed as such, and the 
metal calculated therefrom. 

It will sometimes happen that in analyzing samples which contain 
organic matter of certain kinds, a small amount of carbonaceous matter 
will persist throughout the entire assay, and yield a grayish or brownish 
residue after ignition. In such cases, the cooled residue should be treated 
with a small quantity of ammonium nitrate, and again carefully ignited. 

Separation of Potassium. — The ignited sulphates of the metals obtained 
as above are dissolved in hot water, using at least 20 mils for each decigram 
of potassium oxide present, a few drops of hydrochloric acid added, and 



1028 INORGANIC SECTION 

platinum solution in excess (2.1 grams H 2 PtCl 6 to 10 mils). The solu- 
tion is evaporated on a water-bath to a thick paste, treated with 80 per 
cent alcohol, filtered onto a tared Gooch, washed thoroughly with 80 per- 
cent alcohol both by decantation and on the filter, continuing the washing 
after the filtrate is colorless. Wash five to six times with 10 mils ammo- 
nium chloride saturated with potassium platinic chloride solution, then 
with a further quantity of 80 per cent alcohol, dry at 100° for thirty 
minutes and weigh. * 

Separation of Lithium. — The ignited sulphates obtained as above 
described are dissolved in water, slightly acidified with hydrochloric acid, 
brought to boiling, and barium chloride added gradually, with constant 
stirring, until in excess. The sulphate is allowed to settle out, the solu- 
tion filtered off, the precipitate washed, the barium removed by ammo- 
nium sulphate, the filtrate evaporated, dried at 120°, and ignited below 
redness to remove ammonium salts. The residue is treated with a mix- 
ture of equal volumes absolute alcohol and anhydrous ether, digesting for 
at least twenty-four hours with occasional shaking and thoroughly dis- 
integrating the salts. The liquid is decanted through a covered filter 
and the resdue treated with several portions of the alcohol-ether mixture. 
The filtrate contains the lithium salt, and the metal is estimated by evapo- 
rating the solvent and converting to sulphate. 

DETERMINATION OF LITHIUM AS PHOSPHATE 

The sulphate residue is dissolved in water, treated with an excess of 
sodium phosphate, rendered alkaline with sodium hydroxide, and evapo- 
rated to dryness. The residue is treated with enough water to dissolve 
the soluble salts with the aid of gentle heat, an equal volume of ammonia 
water added, the mixture digested for twelve hours at a gentle heat, 
filtered onto a tared Gooch, and the precipitate washed with an equal 
volume of water and ammonia water. The filtrate and washings are 
evaporated to dryness, the residue treated as before, and if more lithium 
phosphate is obtained it is added to that on the filter, washing as before. 
The precipitate is finally washed with alcohol and dried at 100° to con- 
stant weight. The precipitated normal lithium phosphate has the formula 
2L13PO4+H2O, and the water is completely expelled at 100°. 

DETERMINATION OF POTASSIUM BY PERCHLORIC ACID 

This method appeared in the Chemist Analyst, Dec. 1, 1918. 

The solution of the alkali metals prepared in the usual way is freed 
from sulphates by barium chloride, evaporated to dryness and heated 
until ammonium salts are driven off — below red heat so as not to volatilize 
the potassium chloride. The residue is dissolved in 20 mils hot water, 



METALS AND THEIR COMPOUNDS 1029 

sufficient perchloric acid added to combine with all the bases present, 
evaporated without stirring, cooled, and the residue dissolved in hot 
water. More perchloric acid is added and the solution evaporated until 
the heavy white fumes of perchloric acid are given off. After cooling, 
the residue is treated with 25 mils strong alcohol containing .2 per cent 
HCIO4 (1 mil 60 per cent acid to 300 mils alcohol) breaking up residue 
with stirring rod. The liquid is decanted through a tared Gooch contain- 
ing a mat which has been washed with the above wash alcohol. Wash 
once again with the wash alcohol, decant and transfer the precipitate to 
the crucible. Wash several times with the wash alcohol, dry for an hour 
at 120-130°, cool and weigh as KC10 4 . 

The salt may be washed off the mat with hot water and the crucible 
used repeatedly, 

AMMONIUM 

Ammonia and ammonium salts will be found in a great variety of 
remedies. 

Solution of ammonia gas is used in the preparation of the U. S. P. 
spirit and aromatic spirit, and occurs in liniments. 

Ammonium chloride is an important constituent of throat tablets, 
cough mixtures, and antiseptic tablets. The bromide, carbonate, sali- 
cylate, and valerianate have important though probably less extended 
uses. 

Ammonium salts, notably the citrate, occur in tonic mixtures of the 
beef, iron, and wine, and cod-liver extract type. 

Assay of Spirit of Ammonia. — Two mils of the sample are carefully 
weighed in a stoppered weighing bottle, diluted with 50 mils distilled 
water and titrated with N/2 sulphuric acid, using litmus or methyl red 
as an indicator. 

Estimation of Free Ammonia in Liniments, etc. — The weighed sample 
is introduced into a boiling flask, diluted with water, and distilled into a 
measured volume of N/10 hydrochloric acid or N/2 sulphuric acid colored 
with methyl red. The collecting flask should be watched, and if the color 
changes to yellow, a further measured quantity of acid is added. The 
free ammonia will come over during the first fifteen minutes of the distilla- 
tion. The excess of acid is titrated with standard alkali. 

The distilling flask of the Kjeldahl apparatus furnishes the most satis- 
factory receptacle for conducting this determination. 

Ammonium Salts alone or in Admixture with Other Inorganic Compounds 
or with Non-nitrogenous Organic Substances. — The weighed sample is 
introduced into a boiling flask, diluted with water, treated with an excess 



1030 INORGANIC SECTION 

of concentrated sodium hydroxide and distilled into standard acid as 
directed above. 

Ammonium Salts in Presence of Nitrogenous Organic Substances. — 
This determination is applicable to preparations of beef, iron, and wine 
and cod-liver extracts. 

The weighed sample is introduced into a boiling flask, diluted with 
water, magnesium oxide added, and distilled into standard acid. 

Estimation of Ammonium Chloride in Antiseptic Tablets (Chapin). — 
Into each of two 150-mil Erlenmeyer flasks pipette 5 mils of the tablet 
solution previously prepared for the estimation of mercuric chloride (5 
tablets per 100 mils) and add to each flask 2 mils of a 20 per cent solution 
of potassium iodide. 

Dilute one volume of 37 per cent formaldehyde solution with 3 volumes 
of water, measure 20 mils of the mixture into a small flask, add .5 mil of 
phenolphthalein indicator solution, neutralize with N/10 barium or caustic 
alkali, then flow the solution over the sides of one of the flasks, A, con- 
taining tablet solution -and mix well. To the other flask, B, containing 
tablet solution add about 65 mils water. 

Now add to flask A 25 mils water and titrate with N/10 barium or 
caustic alkali free from carbon dioxide until, by using flask B as a standard 
for comparison, a color change is perceptible (titration A). 

Add methyl red to flask B and titrate with either N/10 acid or alkali 
as needed (titration B). 

To titration A add titration B if performed with acid, or subtracted 
if performed with alkali. The resulting figure multiplied by the factor 
.0214 for strictly N/10 alkali will give the average weight of ammonium 
chloride per tablet. 



TABLES 



ATOMIC WEIGHTS 

Adopted by the International Committee on Atomic Weights (1915) Oxygen = 16 



Name 



Aluminum. 
Antimony . 

Argon 

Arsenic. . . 
Barium. . . 
Bismuth. . . 

Boron 

Bromin 
Cadmium . 
Caesium. . . 
Calcium. . 
Carbon. . . . 
Cerium 
Chlorine. . . 
Chromium . 

Cobalt 

Columbium 
Copper. . . . 
Dysprosium 
Erbium. . . . 
Europium . . 
Fluorine. . . 
Gadolinium 
Gallium 
Germanium 
Glucinum. . 

Gold 

Helium. . . . 
Holmium. . 
Hydrogen . . 
Indium. . . . 

Iodin 

Iridium . . . . 

Iron 

Krypton. . . 
Lanthanum 

Lead 

Lithium. . . 
Lutecium. . 
Magnesium . 
Manganese . 



Symbol 


Atomic 
Weight 


Al 


27.1 


Sb 


120.2 


A 


39.88 


As 


74.96 


Ba 


137.37 


Bi 


208.0 


B 


11.0 


Br 


79.92 


Cd 


112.40 


Cs 


132.81 


Ca 


40.07 


C 


12.00 


Ce 


140.25 


CI 


35.46 


Cr 


52.0 


Co 


58.97 


Cb 


93.5 


Cu 


63.57 


Dy 


162.5 


Er 


167.7 


Eu 


152.0 


F 


19.0 


Gd 


157.3 


Ga 


69.9 


Ge 


72.5 


Gl 


9.1 


Au 


197.2 


He 


3.99 


Ho 


163.5 


H 


1.008 


In 


114.8 


I 


126.92 


Ir 


193.1 


Fe 


55.84 


Kr 


82.92 


La 


139.0 


Pb 


207.10 


Li 


6.94 


Lu 


174.0 


Mg 


24.32 


Mn 


54.93 



Name 



Symbol 



Mercury 

Molybdenum 

Neodymium 

Neon 

Nickel 

Niton (radium emanation) 

Nitrogen 

Osmium 

Oxygen 

Palladium 

Phosphorus 

Platinum 

Potassium 

Praseodymium 

Radium 

Rhodium 

Rubidium 

Samarium 

Scandium 

Selenium 

Silicon 

Silver 

Sodium 

Strontium 

Sulphur 

Tantalum 

Tellurium 

Terbium 

Thallium 

Thorium 

Thulium 

Tin 

Titanium 

Tungsten 

Uranium 

Vanadium 

Xenon 

Ytterbium (NeoytterbiumJ 

Yttrium 

Zinc 

Zirconium 



Hg 
Mo 
Nd 

Ne 

Ni 

Nt 

N 

Os 

O 

Pd 

P 

Pt 

K 

Pr 

Ra 

Rh 

Ru 

Sa 

Sc 

Se 

Si 

Ag 

Na 

Sr 

S 

Ta 

Te 

Tb 

Tl 

Th 

Tm 

Sn 

Ti 

W 

U 

V 

Xe 

YT) 

Y T t 

Zn 

Zr 



Atomic 
Weight 



200.6 
96.0 
144.3 
20.2 
58.68 
222.4 
14.01 
190.9 
16.00 
106.7 
31.04 
195.2 
39.10 
140.6 
226.4 
102.9 
101.7 
150.4 
44.1 
79.2 
28.3 
107.88 
23.00 
87.63 
32.07 
181.5 
127.5 
159.2 
204.0 
232.4 
168.5 
119.0 
48.1 
184.0 
238.5 
51.0 
130.2 
172.0 
89.0 
65.37 
90.6 



1033 



1034 



TABLES 



STANDARD SOLUTIONS 
Standard Sulphuric Acid, Standard Hydrochloric Acid, Standard Oxalic Acid 

Equivalents per 1 mil of standard Acid 
(To find the equivalent of any other normality, point off the proper decimal place or 

divide by the proper factor) 



N Acid, 
gram equiv. 



N/2 Acid, 
gram, equiv. 



N/50 Acid, 
gram equiv. 



Hydrochloric Acid, HC1 

Sulphuric Acid, H 2 S0 4 

Oxalic Acid, H 2 C 2 04+2H 2 

Aconite. Ether soluble alkaloids 

Aconitin, C 34 H 47 0nN 

Ammonia, NH 3 

Ammonium Acetate, NH 4 C 2 H 3 2 

Ammonium Carbonate, (NH 4 ) 2 C0 3 

Ammonium Carbonate, U. S. P., 

NH 4 HC0 3 -NH 4 NH 2 C0 2 

Atropin, Ci 7 H 13 3 N 

Barium Hydroxide, Ba(OH) 2 +8H 2 

Benzaldehyde, C 7 H 6 

Brucin, C 23 H 26 4 N 2 

Calcium Carbonate, CaC0 3 

Calcium Hydroxide, Ca(OH) 2 

Calcium Lactate, Ca(C 3 H 5 0) 3 . 

Calcium Oxide, CaO 

Cephaelin, d 4 Hi 9 2 N 

Chelerythrin, C 2 iH 17 4 N 

Cinchona. Combined alkaloids 

Cinchonidin, Ci 9 H 22 ON 2 

Cinchonin, Ci 9 H 22 ON 2 

Cinnamic Aldehyde, C 9 H 8 

Citral, Ci H 16 O ' 

Cocain, Ci 7 H 2 i0 4 N 

Codein, C 18 H 21 3 N 

Codein, C ]8 H 21 3 N+H 2 

Coniin, C 8 Hi 7 N 

Emetin, Ci 5 H 21 2 N 

Gelsemium Alkaloids 

Hydrastin, C 21 H 21 6 N 

Ipecac. Combined alkaloids 

Lead, Pb 

Lead Acetate, Pb(C 2 H 3 2 ) 2 

Lead Acetate, Pb(C 2 H 3 2 ) 2 +3H 2 

Lead Subacetate, Pb 2 0(C 2 H 3 2 ) 2 

Lead Oxide, PbO 

Lead Peroxide, Pb0 2 

Lithium Carbonate, Li 2 C0 3 

Lithium Citrate, Li 3 C 6 H 5 7 

Lithium Citrate, Li 3 C 6 H 5 7 +4H 2 



0.03647 

0.049045 

0.063025 

0.645 

0.64539 

0.01703 

0.07707 

0.04804 

0.052373 

0.28919 

0.15776 

0.39423 

0.050035 

0.037045 

0.028035 
0.23316 



0.29420 
0.29420 



0.30318 

0.29918 

0.31719 

0.12715 

0.24718 

0.408 

0.38318 

0.240 

0.10355 

0.16257 

0.18960 

0.13706 

0.11155 

0.11955 

0.03694 

0.034977 

0.04699 



0.018235 
0.024523 
0.031512 



0.008515 



0.0530 



0.05454 



0.033015 
0.076 



0.0007294 
0.0009809 
0.001205 

0.012907 



0.0057838 



. 006943 
0.0061841 
0.005884 
0.005884 



0.0060636 



0.002543 



0.0076636 
0.0048034 



TABLES 
STANDARD SOLUTIONS— Continued 



1035 



N Acid, 
gram equiv. 



N/2 Acid, 
gram equiv. 



N/50 Acid, 
gram equiv. 



Lithium Salicylate, LiC 7 H 5 3 

Magnesium Carbonate, (MgC0 3 ) 4 Mg(OH) 2 -f 5H 2 

Magnesium Hydroxide, Mg(OH) 2 

Magnesium Oxide, MgO 

Manganese Dioxide, Mn0 2 

Morphin, C 17 H 19 3 N 

Morphin, C 17 H 19 3 N+H 2 

Mydriatic Alkaloids combined 

Nitrogen, N 

Nux Vomica Alkaloids combined 

Physostigmin, d 5 H 2 i0 2 N 3 

Pilocarpin, CuHi 6 2 N 2 

Pomegranate Bark Alkaloids 

Potassium and Sodium Tartrate, KNaC 4 H 4 6 +4H 2 

Potassium and Sodium Tartrate, Anhydrous 

Potassium Acetate, KC 2 H 3 2 

Potassium Bicarbonate, KHC0 3 

Potassium Bitartrate, KHC 4 H 4 06 

Potassium Carbonate, K 2 C0 3 

Potassium Citrate, K 3 C 6 H 5 7 +H 2 

Potassium Citrate, Anhydrous 

Potassium Hydroxide, KOH 

Potassium Permanganate, KMn0 4 

Quinin, C 20 H 24 O 2 N 2 

Sabadilla Alkaloids 

Sanguinaria Alkaloids 

Sodium Acetate, NaC 2 H 3 2 +3H 2 

Sodium Acetate, Anhydrous 

Sodium Benzoate, NaC 7 H 5 2 

Sodium Bicarbonate, NaHC0 3 

Sodium Biborate, Na-2B 4 O7+10H 2 O 

Sodium Biborate, Anhydrous 

Sodium Cacodylate, Na(CH 3 ) 2 As0 2 

Sodium Carbonate, Na 2 C0 3 +H 2 

Sodium Carbonate, Anhydrous 

Sodium Citrate, Na 3 C 6 H 5 7 +2H 2 

Sodium Citrate, Anhydrous 

Sodium Glycerophosphate, NaoC 3 H 7 P0 6 

Sodium Hydroxide, NaOH 

Sodium Salicylate, NaC 7 H 5 3 

Sodium Tartrate, Na 2 C 4 H 4 6 +2H 2 

Strontium Salicylate, Sr(C 7 H 5 3 ) 2 +2H 2 

Strontium Salicylate, Anhydrous 

Strychnin, C 2 iH 22 2 

Zinc Oxide, ZnO 

Zinc Permanganate, Zn(Mn0 4 ) 2 +6H 2 



0.14398 
0.04857 

0.02016 

0.043465 

0.28516 

0.30318 

0.2092 

0.014 

0.364 

0.27520 

0.20815 

0.147 

0.14110 

0.09812 
0.10011 
0.18814 
0.06910 
0.10812 

0.05611 

0.031606 

0.32421 

0.5984 

0.35 

0.13607 



0.08401 

0.19108 

0.101 

0.1600 

0.06201 

0.0530 



0.04001 
0.16004 



0.33420 

0.040685 

0.040842 



0.0148 



0.07055 

0.052533 

0.04906 

0.050055 

0.09407 

0.03455 

0.05406 

0.051057 

0.028055 



0.068035 
0.04101 
0.07202 
0.042005 



0.031005 

0.02650 

0.04901 

0.04301 

. 10805 

0.020005 

0.08002 

0.057515 

0.099435 

0.9043 



0.0057032 
0.0060636 



0.005504 
0.004163 



0037628 



0.0062842 



0.006684 



1036 



TABLES 



STANDARD SOLUTIONS 

Standard Potassium Hydroxide, Standard Sodium Hydroxide, Standard 

Alcoholic Alkali 

Equivalent per 1 mil of Standard Alkali 



N Alkali, 
gram equiv. 



N/2Alkali, 
gram equiv. 



N 50 Alkali, 
gram equiv. 



Potassium Hydroxide, KOH 

Sodium Hydroxide, NaOH 

Acetic Acid, HC 2 H 3 2 

Acetic Acid Anhydride, (CH 3 CO) 2 

Ammonia, NH 3 

Ammonium Chloride, NH 4 C1 

Betaeucain Hydrochloride, C 15 H 2 i0 2 N • HC1 

Boric Acid, H 3 B0 4 

Borneol, Ci Hi 8 O 

Bornyl Acetate, Ci H 17 C 2 H 3 O 2 

Chloral Hydrate, C 2 H0C1 3 +H 2 

Carvone, CioH x4 

Camphor, Ci H 16 O 

Citric Acid, H 3 C 6 H 5 7 +H 2 

Formaldehyde, CH 2 

Hydriodic Acid, HI 

Hydrobromic Acid, HBr 

Hydrochloric Acid, HC1 

Hypophosphorous Acid, HPH 2 2 

Lactic Acid, HC 3 H 5 3 

Menthol, C 10 H 20 O 

Menthyl Acetate, C 1C H 19 C 2 H 3 

Methyl Salicylate, CH 3 C 7 H 5 

Nitric Acid, HN0 3 

Oxalic Acid, H 2 C 2 4 +2H 2 

Paraformaldehyde, (CH 2 0) 3 

Phosphoric Acid, H 3 P0 4 . To form K 2 HP0 4 with 

Phenolphthalein 

Potassium Bitartrate, KHC 4 H 4 6 

Santalol, Ci 5 H 26 

Sodium Bitartrate, NaHC 4 H 4 6 +H 2 0. 

Salicylic Acid, C 7 H 7 3 

Sulphuric Acid, H 2 S0 4 

Sulphur Trioxide, S0 3 

Tartaric Acid, H 2 C 4 H 4 6 

Trichloracetic Acid, HC 2 2 C1 3 



0.05611 
0.04001 
0.06003 
0.05102 
0.01703 
0.05350 
0.28365 
0.06202 



0.1654 

0.15 

0.1509 

0.07003 

0.03002 

0.12793 

0.08093 

0.03647 

0.06606 

0.09005 



0.06302 

0.063025 

0.03002 

0.04903 
0.18814 

0.1901 

0.138 

0.049045 

0.040035 

0.07503 

. 16339 



0.02806 

0.020005 

0.03002 



0.03101 
0.07707 
0.09808 



0.03502 

0.06397 
0.04047 
0.01824 
0.03303 
0.04503 
0.07808 
0.09909 
0.07603 
0.03151 
0.03153 



0.02452 
0.09407 
0.111105 
0.09503 

0.024523 

0.02002 

0.03751 

0.08170 



0.0011222 
0.0008002 



0.0009809 



TABLES 



1037 



FEHLING'S SOLUTION 
Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram, equiv. 



Copper Sulphate, CuS0 4 +5H 2 

Copper Tartrate, CuC 4 H 4 6 +3H 2 

Cane Sugar (Sucrose), C12H22O11 (after inversion) 

Glucose, Anhydrous, C 6 Hi 2 6 

Lactose, Anhydrous, Ci 2 H 22 0ii 



0.03466 

0.03688 

0.00475 

0.005 

0.00678 



BARIUM HYDROXIDE 
Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram, equiv. 



Barium Hydroxide, Ba(OH) 2 +8H 2 
Ammonium Benzoate, NH4C7H5O1! . . 
Ammonium Salicylate, NH4C7H5O3 . 

Benzoic Acid, C 7 H 6 2 

Hydrochloric Acid, HC1 

Salicylic Acid, C 7 H 6 3 

Sulphuric Acid, H 2 S0 4 



0.15776 
0.13908 
0.15508 
0.12205 
0.03647 
0.13805 
0.049045 



BROMIN. (KOPPESCHAAR'S SOLUTION) 

Usually used as N/10 
Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram equiv. 



Bromin, Br 

Carbolic Acid, C 5 H 6 OH 

Orcin, C 7 H 6 (OH) 2 

Resorcinol, C 6 H 4 (OH) 2 

Sodiumphenolsulphonate, NaC 6 H 5 4 S +2H>0 
Sodiumphenolsulphonate, Anhydrous 



0.07992 

0.01568 

0.02068 

0.01834 

0.058035 

0.04903 



1038 



TABLES 



IODIN 

Usually employed as N/10 
Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram equiv. 



Iodin, I 

Acetone, (CH 3 ) 2 CO 

Antimony Trioxide, Sb 2 3 

Antimony and Potassium Tartrate, K(SbO)C4H40 6 +2H 2 

Arsenic, As (in arsenous compounds) 

Arsenic Iodide, Asl 3 

Arsenic Trioxide, As 2 3 

Calcium Sulphide, CaS 

Formaldehyde, HCHO 

Iron, Fe 

Hexamethylenetetramine, (CH 2 )6N 4 

Mercurous Chloride, HgCl 

Mercurous Iodide, Hgl 

Mercury, Hg (in mercurous compounds) 

Methyl Salicylate, CH 3 C 7 H 5 3 

Potassium Sulphite, K 2 S0 3 +2H0 2 

Sodium Bisulphite, NaHS0 3 . 

Sodium Sulphite, Na 2 S0 3 

Sodium Thiosulphate, Na 2 S 2 3 +5H 2 

Sodium Thiosulphate, Anhydrous 

Sulphur Dioxide, S0 2 



0.12692 

0.009675 

0.072 

0.16617 

0.03748 

0.22786 

0.04948 

0.03607 

0.015 

0.2792 

0.01167 

0.23606 

0.32752 

0.2006 

0.02535 

0.09715 

0.05204 

0.06304 

0.24822 

0.15814 

0.032035 



POTASSIUM DICHROMATE 
Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram equiv. 



Potassium Dichromate, K 2 Cr 2 7 

Glycerin, C 3 H 6 (OH) 3 

Ferrous Carbonate, FeC0 3 

Ferrous Sulphate, FeS0 4 +7H 2 

Ferrous Sulphate, Anhydrous 

Iron, Fe (in Ferrous Compounds) 

Lactic Acid, HC 3 H 5 3 

Sodium Thiosulphate, Na 2 S 2 3 +5H 2 



0.049033 

0.06549 

0.11584 

0.27802 

0.15191 

0.05584 

0.02254 

0.24822 



TABLES 



1039 



POTASSIUM PERMANGANATE 

Usually employed as N/10 
Equivalent per 1 Mil of Standard Solution 



Potassium Permanganate, KMn0 4 

Calcium Dioxide, Ca0 2 

Calcium Oxide CaO, (as oxalate) . 

Ferrous Carbonate, FeC0 3 

Ferric Oxide, FesOs 

Ferrous Oxide, FeO 

Ferrous Sulphate, FeS0 4 +7H_0. . 
Ferrous Sulphate, Anhydrous .... 

Glycerin, C 3 H 5 (OH) 3 

Hydrogen Dioxide, H 2 2 

Iron in ferrous compounds, Fe . . . 

Magnesium Dioxide, Mg0 2 

Oxalic Acid, H 2 C 2 4 +2H 2 

Oxygen, 

Potassium Chlorate, KC10 3 

Sodium Dioxide, Na 2 2 

Sodium Chlorate, NaC10 3 

Sodium Nitrite, NaN0 2 

Sodium Oxalate, Na^C^ 

Strontium Dioxide, Sr0 2 

Zinc Dioxide, Zn0 2 



N Solution, 
gram equiv. 



0.031606 

0.036 

0.28035 

0.11584 

0.07985 

0.07184 

0.27802 

0.15191 

0.046 

0.017008 

0.05584 

0.02 

0.063025 

0.008 

0.020427 

0.03786 

0.017743 

0.034505 

0.067 

0.061 

0.048 



POTASSIUM SULPHOCYANATE 

Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram equiv. 



Potassium Sulphocyanate, KSCN 

Mercuric Iodide, Hgl 2 

Mercuric Nitrate, Hg(N0 3 ) 2 

Mercuric Oxide, HgO 

Mercury, Hg 

Silver, Ag 

Silver Nitrate, AgN0 3 

Silver Oxide, Ag 2 



0.09718 
0.22722 
. 16231 
0.1083 
0.1003 
. 10788 
0.16989 
0.11588 



1040 



TABLES 



SILVER NITRATE 

Usually employed as N/10 
Equivalent per 1 Mil of Standard Solution 



N Solution, 
gram equiv. 



Silver Nitrate, AgN0 3 

AUyl Iso-thiocyanate, C3H5SCN 

Ammonium Bromide, NHJBr 

Ammonium Chloride, NH 4 C1 

Ammonium Iodide, NHJ 

Arsenous Iodide, Asl 3 

Bromin, Br 

Calcium Bromide, CaBr 2 +2H 2 

Calcium Bromide, Anhydrous 

Calcium Chloride, CaCl 2 +2H 2 

Calcium Chloride Anhydrous 

Calcium Hypophosphite, Ca(PH 2 2 ) 2 

Chlorine, CI 

Ferrous Bromide, FeBr 2 

Ferrous Iodide, Fel 2 

Hydriodic Acid, HI 

Hydrobromic Acid, HBr 

Hydrochloric Acid, HC1 

Hydrocyanic Acid, HCN (to first formation of precipitate) . 
Hydrocyanic Acid, (with potassium chromate as indicator) . 

Iodin, I 

Lithium Bromide, LiBr 

Lithium Chloride, LiCl 

Phosphoric Acid, H3PO4 

Potassium Bromide, KBr 

Potassium Chloride, KC1 

Potassium Cyanide, KCN (to first formation of precipitate) 

Potassium Hypophosphite, KPH 2 2 

Potassium Iodide, KI 

Potassium Nitrate, KNO3 > 

Potassium Sulphocyanate, KSCN 

Sodium Bromide, NaBr 

Sodium Chloride, NaCl 

Sodium Cyanide, NaCN (to first formation of precipitate) . 

Sodium Hypophosphite, NaPH 2 2 +H 2 

Sodium Iodide, Nal 

Sodium Nitrate, NaN0 5 

Sodium Phosphate, Na 2 HP0 4 +12H 2 

Sodium Phosphate, Anhydrous 

Strontium Bromide, SrBr 2 +6H 2 r 

Strontium Chloride, SrCl 2 +6H 2 

Strontium Iodide, SrI 2 +6H 2 

Zinc Chloride, ZnCl 2 



16989 

04956 

09796 

05350 

14496 

15191 

07992 

11797 

099955 

073511 

0555 

02836 

03546 

10784 

15484 

12793 

08093 

03647 

05404 

02702 

12692 

08686 

0424 

032687 

11902 

07456 

13022 

03472 

16602 

10111 

09718 

10292 

05846 

09802 

035357 

14992 

08501 

11941 

04735 

17779 

13332 

22479 

068145 



TABLES 



1041 



SODIUM CHLORIDE 
Equivalent per 1 Mil of Standard Solution 



Sodium Chloride NaCl. 

Silver, Ag 

Silver Nitrate, AgN0 3 . 



N Solution, 
gram equiv. 



. 05846 
0.10788 
0.16989 



Silver Oxide, A&O 0.11588 

SODIUM THIOSULPHATE 

Usually employed as N/10 solution 
Equivalent per 1 Mil of Standard Solution 



X Solution, 
gram equiv. 



Sodium Thiosulphate, Xa 2 S 2 3 +5H 2 0.24822 

Bromin, Br | .07992 

Chlorine, CI 0.03546 

Chromium Trioxide, Cr0 3 : 0.03333 

Copper Sulphate, CuS0 4 +5H 2 j 0.24972 

Copper Sulphate, Anhydrous ! . 15964 

Iodin, I | 0. 12692 

Iodin, I (from thyroid glands) 

Iodin, I (thymol iodide) 0.02115 

Iron, Fe (in ferric salts) . 05584 

Lead Peroxide, Pb0 2 0. 1195 

Mercuric Chloride, HgCl 2 0.271 

Potassium Bromate, KBr0 3 0.027837 

Potassium Dichromate, L>Cr 2 7 0.049033 

Sodium Arsenate, Na 2 HAs0 4 +7H,0 . 15604 

Sodium Arsenate, Anhydrous . 092985 

Salicylic Acid, C 7 H 6 3 0.06885 

Thymol, CioH 14 0.075056 



X 2 Solution, 
gram equiv. 



0.12411 



0.06346 
0.01058 



1042 



TABLES 



REAGENTS 

Test Solution and Indicators 

The solutions have been made to conform as nearly as practicable with those given 
in the Pharmacopoeia, and in most cases directions for preparation are given on the basis 
of 100-mil quantities. 

Whenever the word " water " is used it is understood to mean " distilled water." 
Acid, Acetic Glacial. 

35 mils glacial acid with 65 mils water. 
6 mils glacial with 94 mils water. 



Acid, Acetic, 36 per cent. 

Acid, Acetic Dilute, 10 per cent. 

Acid, Hydrochloric Cone. 

Acid, Hydrochloric Dilute, 10 per cent. 



Acid, Nitric Cone. 

Acid, Nitric Dilute, 10 per cent. 

Acid, Sulphuric Cone. 

Acid, Sulphuric Dilute, 10 per cent. 

Alcohol, 95 per cent. 

Ammonia Water (stronger) 28 per cent. 

Ammonia Water Dilute, 10 per cent. 

Ammonium Carbonate. 



Ammonium Molybdate. 



Ammonium Oxalate. 
Ammonium Sulphate. 
Ammonium Sulphide. 



Ammonium Validate. 

(Mandelin's Reagent.) 
Azolitmin. 



Barium Chloride. 
Barium Hydroxide. 
Bromin Water. 

Cadmium and Potassium Iodide. 

Cadmium Chloride. 
Calcium Chloride. 
Calcium Hydroxide. 



30 mils hydrochloric acid cone, with 70 mils 
water. 

11 mils nitric acid cone, with 89 mils water. 

7 mils sulphuric acid cone, with 93 mils water. 



36 mils stronger ammonia water with 64 mils 
water. 

20 grams ammonium carbonate U. S. P. dis- 
solved in 20 mils ammonia water 10 per cent 
and 80 mils water. 

10 grams molybdic acid dissolved in 42 mils 
ammonia water 10 per cent and poured into 
a mixture of 63 mils water and 63 mils nitric 
acid cone. 

4 grams dissolved in 100 mils water. 
10 grams dissolved in 100 mils water. 

6 mils ammonia water . 10 per cent are satu- 
rated with hydrogen sulphide and then diluted 
with 40 mils ammonia water 10 per cent. To 
prepare the yellow ammonium sulphide add 
1 to 2 grams of sulphur and shake until dis- 
solved. 

1 gram dissolved in 100 mils sulphuric acid cone. 

1 gram dissolved in 80 mils water and 20 mils 
alcohol. Place in tightly stoppered bottle 
and expose to temperature of steam for one 
hour. 

10 grams dissolved in 100 mils water. 

Saturated solution. 

3 mils dissolved in 100 mils water. Freshly pre- 
pared. 

5 grams of equal parts by weight of the two salts 
dissolved in 100 mils water. 

10 grams dissolved in 100 mils water. 
10 grams dissolved in 100. mils water. 
Saturated solution. 



TABLES 



1043 



Calcium Hypochlorite. 



Calcium Sulphate. 
Chlorine Water. 



Cobalt Nitrate. 
Cobaltous Chloride. 

Cochineal. 

Congo Red. 

Copper Acetate. 

Copper Ammonium Sulphate. 



Copper Sulphate. 
Fehling's Solution. 



Formaldehyde-Sulphuric Acid. 

(Marquis Reagent) 
Fuchsin-Sulphurous Acid. 



Gold Chloride. 

Hematoxjdin. 

Iodeosin. 

Iodin (Wagner's Reagent). 

Iron Chloride (Ferric). 

Iron Sulphate (Ferrous). 

Lead Acetate. 

Lead Acetate. Alcoholic. 

Lead Subacetate. 



Litmus. 



10 grams triturated with 20 mils water, filtered 
and repeated and the filtrate made up of 100 
mils. 

Saturated solution. 

0.5 gram potassium chlorate treated with 2 mils 
hydrochloric acid cone, in a flask fitted with 
a perforated stopper, warmed on steam-bath 
and when the flask is full of gas add 100 mils 
water. 

10 grams dissolved in 100 mils water. 

2 grams dissolved in 100 mils water and 1 mil 
hydrochloric acid. 

1 gram macerated with 20 mils alcohol and 60 
mils water for four days. Then filtered. 

0.5 gram dissolved in 90 mils water and 10 mils 
alcohol. 

1 gram dissolved in 1000 mils water. If solu- 
tion becomes cloudy add few drops acetic 
acid until clear. 

To be freshly made. To a solution of copper 
sulphate add ammonia until precipitate first 
formed is not quite dissolved. 

10 grams dissolved in 100 mils water. 

(1) 7 grams copper sulphate dissolved in 100 
mils water. 

(2) 35 grams Rochelle salt and 10 grams sodium 
hydroxide dissolved in 100 mils water. 

10 mils formaldehyde solution in 50 mils sul- 
phuric acid. 

0.5 gram fuchsin and 9 grams sodium bisulphite 
dissolved in 500 mils water and treated with 
10 mils hydrochloric acid. 

3 grams dissolved in 100 mils water. 
0.2 gram dissolved in 100 mils alcohol. 
0.1 gram dissolved in 100 mils alcohol. 

2 grams with 6 grams potassium iodide dis- 
solved in 100 mils water. 

10 grams dissolved in 100 mils of recently boiled 

water. 
To be freshly made; 1 gram dissolved in 10 mils 

of recently boiled water. 
10 grams dissolved in 100 mils water. 

3 grams of crystals dissolved in 100 mils alcohol. 
18 grams lead acetate dissolved in 70 mils water, 

added to 11 grams of lead oxide (Litharge, 
PbO) in a porcelain dish, boiled for one-half 
hour, filtered and made up to 100 mils. 
Exhaust the powder three times with boiling 
alcohol, each treatment consuming an hour. 
Treat residue with an equal weight of cold 
water and filter. Then exhaust with five times 
its weight of boiling water, cool and filter. 



1044 

Magnesia Mixture. 



Magnesium Sulphate. 

Mercuric Chloride. 

Mercuric Chloride. Alcoholic. 

Mercuric Nitrate. 

Mercuric-Potassium Iodide. 
(Mayer's Reagent). 



Mercurous Nitrate. 

Methyl Orange. 
Methyl Red. 
Millon's Reagent. 



Oxalic Acid. 
Palladous Chloride. 
Phenolphthalein. 

Phosphomolybdic Acid. 
(Sonnenschein's Reagent). 



Phosphotungstic Acid. 
(Scheibler's Reagent). 

Picric Acid (Hager's Reagent). 
Platinic Chloride. 
Potassium Bromide-Br ornate. 



Potassium-cadmium Iodide. 
(Marine's Reagent). 

Potassium Carbonate. 

Potassium Chromate. 
Potassium Cyanide. 

Potassium Dichromate. 
Potassium Ferricyanide. 

Potassium Ferrocyanide. 
Potassium Hydroxide. 
Potassium Iodide. 
Potassium Permanganate. 



TABLES 

10 grams magnesium sulphate and 20 grams 
ammonium chloride dissolved in 80 mils water 
and 42 mils ammonia water 10 per cent added. 

10 grams dissolved in 100 mils water. 

5 grams dissolved in 100 mils water. 

6 grams dissolved in 100 mils alcohol 95 per 
cent. 

40 grams red mercuric oxide dissolved in 45 
grams of nitric acid (cone.) and 15 mils water. 

1.3 grams mercuric chloride dissolved in 60 mils 
water added to 5 grams potassium iodide dis- 
solved in 10 mils water and made up to 100 
mils. 

10 grams in 100 mils water. Keep over metallic 
mercury. 
1 gram dissolved in 1000 mils water. 

0.2 gram dissolved in 100 mils alcohol. 

10 grams mercury dissolved in 10 grams nitric 
acid (cone.) with the aid of heat, and then 
diluted with two volumes of water. 

5 grams dissolved in 100 mils water. 

5 grams dissolved in 100 mils water. 

1 gram dissolved in 50 mils alcohol and 50 mils 
water added. 

Prepare ammonium phosphomolybdate and, 
after washing with water, boil with nitric acid 
and expel ammonia, evaporate to dryness and 
dissolve in 10 per cent nitric acid. 

20 grams sodium tungstate and 15 grams sodium 
phosphate dissolved in 100 mils water con- 
taining a little nitric acid. 

1 gram dissolved in 100 mils water. 
13 grams dissolved in 100 mils water. 

To a concentrated solution of potassium hydrox- 
ide add bromine to saturation, boil off excess 
and dilute with an equal volume of water. 

2 grams cadmium iodide added to a boiling solu- 
tion of 4 grams of potassium iodide in 12 mils 
water and mixed with an equal volume of 
saturated solution potassium iodide. 

10 grams recently dehydrated at 130° C, dis- 
solved in 100 mils water. 

10 grams dissolved in 100 mils water. 

To be freshly prepared. 1 gram dissolved in 10 
mils water. 

10 grams dissolved in 100 mils water. 

10 grams dissolved in 100 mils water, freshly 
made. 

10 grams dissolved in 100 mils water. 

6 grams dissolved in 94 mils water. 
20 grams dissolved in 100 mils water. 
0.5 gram dissolved in 100 mils water. 



TABLES 



1045 



Potassium Sulphate. 
Potassium Sulphocyanide. 
Pyrogallol Alkaline. 



Resorcinol. 
Rosolic Acid. 

Silver Nitrate. 

Silver Nitrate, Ammoniacal. 



Silver Sulphate. 

Sodium Acetate. 
Sodium Bisulphite. 



Sodium Bitartrate. 



Sodium Carbonate. 
Sodium-Cobaltic Nitrite. 



Sodium Cyanide. 

Sodium Hydroxide. 
Sodium Hypobromite. 



Sodium Hypochlorite. 



Sodium Nitroprusside. 

Sodium Phosphate. 

Sodium and Potassium Tartrate. 

(Rochelle Salt). 
Sodium Sulphide. 
Sodium Tartrate. 
Sodium Thiosulphate. 
Stannous Chloride. 



1 gram dissolved in 100 mils water. 
1 gram dissolved in 100 mils water. 
To be freshly made as wanted; 14 mils 25 per 

cent pyrogallol in water and 86 mils 60 per 

cent potassium hydroxide. 
1 gram dissolved in 100 mils water. 
1 gram treated with 10 mils alcohol followed by 

100 mils water. 
5 grams dissolved in 100 mils water. 

5 grams silver nitrate dissolved in 100 mils water 
and treated with ammonia water 10 per cent 
until precipitate is not quite redissolved. 

1 gram treated with 100 mils of water. To be 
filtered as used. 

10 grams dissolved in 100 mils water. 

To be freshly made; 30 grams dissolved in 100 
mils water. If sulphur dioxide odor is strong 
add 20 per cent sodium hydroxide until 
scarcely noticeable. 

3.5 grams tartaric acid boiled with 80 mils water, 
sodium carbonate added until neutral and 
then 3.5 grams tartaric acid added and solu- 
tion made up to 100 mils. 

10 grams dissolved in 100 mils water. 

4 grams cobalt nitrate and 10 grams sodium 
nitrite dissolved in 50 mils water, 2 mils acetic 
acid 36 per cent added and then water to 100 
mils. 

To be freshly prepared. 1 gram dissolved in 10 
mils water. 

6 grams dissolved in 94 mils water. 

1 mil bromin dissolved in 15 mils water con- 
taining 4 grams sodium hydroxide, then 
diluted to 20 mils. To be freshly prepared. 

9 grams calcium hypochlorite triturated with 
20 mils water, filtered and repeated, and 
washed with 10 mils water, filtrate mixed 
with 6.5 sodium carbonate monohydrated 
dissolved in 30 mils water, filtered, washed 
and made up to 100 mils. Freshly prepared. 

1 gram dissolved in 10 mils water. Freshly pre- 
pared. 

10 grams dissolved in 100 mils water. 
10 grams dissolved in 100 mils water. 

10 grams dissolved in 100 mils water. 

10 grams dissolved in 100 mils water. 

2.5 grams dissolved in 100 mils water. 

Pure tin boiled with hydrochloric acid cone, 
having metal in excess; when saturated, crys- 
tals will form, which are separated and drained 
and dissolved in 10 parts of water and the 



1046 



TABLES 



Starch. 
Sulphanilic Acid. 



Sulphomolybdic Acid. 

(Froehde's Reagent). 
Tannic Acid. 

Tartaric Acid. 
Turmeric. 



solution preserved in a well-stoppered bottle 

containing tin foil. 
0.5 gram starch mixed with 10 mils water and 

added to 90 mils boiling water. 
0.5 gram dissolved in a mixture of 15 mils 

glacial acetic acid and 135 mils recently 

boiled water. 
10 grams molybdic acid or sodium molybdate 

dissolved in 100 mils sulphuric acid cone. 
10 grams dissolved in 10 mils alcohol and 90 

mils water added. 
10 grams dissolved in 30 mils water. 
Powder is digested with several portions of 

water which are discarded. Then treated 

with six times its weight of alcohol for several 

days and filtered. 



TABLES 



1047 



EQUIVALENTS OF WEIGHTS AND MEASURES 
From 480 Grains Down 



Grains 


Metric weight 
and measure. 
Gram or cm. 


1 

Minims (of 
Water at 4° C.) 


Grains 


Metric weight 
and measure, 
Gram or cm. 


Minims (of 
Water at 4° C.) 


480 


31 . 103 


504.8 


240 


15.552 


252.4 


478.4 


31 


503.1 


231.5 


15 


243.5 


475.4 


30.805 


500 


228.2 


14.786 


240 


463.0 


30 


486.9 


218.75 


14.175 


230.1 


456.4 


29 . 573 


480 


216.1 


14 


227.2 


450 


29.160 


473.3 


210 


13.608 


220.9 


447.5 


29 


470.7 


200.6 


13 


211.0 


437.5 


28.350 


460.1 


199.7 


12.938 


210 


432.1 


28 


454.5 


185.2 


12 


194.8 


427.9 


27 . 725 


450 








420 


27.216 


441.7 


180 


11.664 


189.3 


416.7 


27 


438.2 


171.1 


11.090 


180 


401.2 


26 


422.0 


169.8 


11 


178.5 


399.3 


25.876 


420 


154.3 


10 


162.3 


390 


25.272 


410.2 


150 


9.720 


157.8 


385.8 


25 


405.8 


142.6 


9.242 


150 


380.3 


24.644 


400 


138.9 


9 


146.1 


370.8 


24.028 


390 


123.5 


8 


129.8 


370.4 


24 


389.5 








360 


23.328 


378.6 


120 


7.776 


126.2 


354.9 


23 


373.3 


114.1 


7.393 


120 


342.3 


22.180 


360 


109.37 


7.087 


115.0 


339.5 


22 


357.1 


108.0 


7. 


113.6 


330 


21.384 


347.1 


100 


6.480 


105.2 


324.1 


21 


340.8 


95.1 


6.161 


100 


313.8 


20.331 


330 


92.6 


6 


97.4 


308.6 


20 


324.6 


80 


5.184 


84.1 








77.2 


5. 


81.2 








76.1 


4.929 


80 








61.7 


4 


64.9 


300 


19 . 440 


■ " ■ 
315.5 


60 


3.888 


63.1 


293.2 


19 


308.4 


57.0 


3.697 


60 


285.2 


18.483 


300 


54.69 


3.544 


57.5 


277.8 


18 


292.2 


47.5 


3.081 


50 


270 


17.496 


284.0 


50. 


3.240 


52.6 


262.4 


17 


275.9 


46.3 


3 


48.7 


256.7 


16.635 


270 


42.8 


2.772 


45 


246.9 


16 


259.7 


40 


2.592 


42.1 








38.0 


2.464 


40. 








33.3 


2.156 


35 








30.9 


2 


32.5 



1048 TABLES 

EQUIVALENTS OF WEIGHTS AND MEASURES— Continued 






Grains 


Metric weight 
and measure, 
Gram or cm. 


Minims (of 
Water at 4° C.) 


Grains 


Metric weight 
and measure, 
Gram or c.c. 


Minims (of 
Water at 4° C.) 


30 


1.944 


31.55 


10 


0.648 


10.52 


28.52 


1.848 


30 


9.51 


0.616 


10 


23.77 


1.540 


25 


9 


0.583 


9.47 


20 


1.296 


21.00 


8.56 


0.554 


9 


19.02 


1.232 


20 


8 


0.518 


8.41 


15.4324 


1 


16.23 


7.71 


0.5 


8.12 








7.61 


0.493 


8 








7 


0.454 


7.36 








6.66 


0.431 


7 








6 


0.389 


6.31 








5.70 


0.370 


6 


15 


0.972 


15.78 


5 


0.324 


5.26 


14.26 


0.924 


15 


4.75 


0.308 


5 


14 


0.907 


14.72 


4 


0.259 


4.21 


13.31 


0.863 


14 


3.80 


0.246 


4 


13 


0.842 


13.67 


3 


0.194 


3.16 


12.36 


0.801 


13 


2.85 


0.185 


3 


12 


0.778 


12.62 


2 


0.130 


2.10 


11.41 


0.739 


12 


1.90 


0.123 


2 


11 


0.713 


11.57 


1 


0.06480 


1.0517 


10.46 


0.678 


11 


0.9508 


0.06161 


1 



TABLES 



1049 



EQUIVALENT WEIGHTS AND MEASURES 
From 5 Grains Down 





Grains 


Grams 


Grains 


Grams 


In decimal 
fractions 


In common 

fractions 

(Approximate) 


In decimal 
fractions 


In common 

fractions 

(Approximate) 


0.324 


5 


5 


0.0285 


0.44 


7/16 


0.291 


4.5 


H 


0.0259 


0.40 


2/5 


0.259 


4 


4 


0.0246 


0.38 


3/8 


0.227 


3.5 


3* 


0.0201 


0.31 


5/16 


0.194 


3 


3 


0.0162 


0.25 


1/4 


0.162 


2.5 


9! 


0.0123 


0.19 


3/16 


0.130 


2 


2 


0.0084 


0.13 


1/8 


0.097 


1.5 


H 


0.0039 


0.06 


1/16 


0.065 


1 


l 


0.0032 


0.05 


1/20 








0.0026 


0.04 


1/25 








0.0022 


0.033 


1/30 






0.0609 


0.94 


15/16 


0.0018 


0.028 


1/36 


0.0583 


0.90 


9/10 


0.0016 


0.025 


1/40 


0.0570 


0.88 


7/8 


0.0013 


0.02 


1/50 


0.0531 


0.82 


13/16 


0.0011 


0.017 


1/60 


0.0518 


0.80 


4/5 


0.0010 


0.015 


1/64 


0.0486 


0.75 


3/4 


0.0006 


0.01 


1/100 


0.0447 


0.69 


11/16 


0.0005 


0.008 


1/128 


0.0408 


0.63 


5/8 


0.0004 


0.0065 


1/160 


0.0363 


0.56 


9/16 


0.0003 


0.005 


1/210 


0.0324 


0.5 


1/2 


0.0002 


0.003 


1/320 








0.0001 


0.0015 


1/640 



INDEX 



Abies balsamea, 486 

— fraseri, 486 

— picea, 486 
Abrastol, 784 
Absinthe, 391, 615 
Absinthiin, 394 
Acacia, 463 

Acer spictum, 446 
Acetaldehyde, 585 
Acetamide, 821 
Acetanilid, 833 

— separation of from caffein, 837 

antipyrin, 839 

quinin sulphate, 841 

morphin, 843, 847 

salicylate, 845 

— estimation of in liquid headache 

tures, 849 
Acetates, assay of, 630 
Acetone, 600 

— determination of, 603 
in presence of ethyl alcohol, 

— resorcinol, 604 
Acetopiperon, 359 
Acetozone, 569 
Acetphenetidin, 854 

— separation of from caffein, 857 

and codein, 858 

salol, 859 

quinin, 863 

■ acetanilid, 864 

and antipyrin, 866 

Acetylparaminophenol salicylate, 682 
Acoin, 141 
Aconite, assay, 26 
Acid, Abietic, 488 

— Acetic, 629 

— Acetyl Salicylic, 680, 686 
— • Aconitic, 270, 657 

— Adonidic, 339 

— Anacardic, 700 

— Angelic, 640 



604 



685 



Acid, Arachidic, 633 

— Arsanilic, 876 

— Asparaginic, 647 

— Atropic, 111, 669 

— Barbituric, 825 

— Behenic, 633 

— Benzoic, 659 

estimation of, 662 

separation of from cinnamic, 663 

salicylic, 662 

— Boric, 966 

estimation of, 966 

— Cacodylic, 973 

— Caffeic, 700 

— Caincic, 701 

— Camphoric, 612 

— Camphoronic, 613 

— Carbolic, 754 
estimation of, 756 

of in presence of alcohol, 541 

— Cerotic, 634 

— Chlorogenic, 297 

— Cholalic, 723 

— Chromic, 1012 

— Chrysophanic, 366, 367, 374 

— Cinnamic, 362, 668 

estimation of in aromatic balsams, 

715 
aldehyde, 595 

— Citric, 654 

estimation of, 656 

— Coumaric, 341, 362, 691 

— Cresylic, 758 

— Cro tonic, 640 

— Dihydroxycinnamic, 387, 450 

— Dimethoxycinnamic, 444 

— Ellagic, 432, 694 

— Embelic, 701 

— Ferulic, 507, 692 

— Filicic, 398, 701 

— Formic, 626 



1051 



1052 



INDEX 



Acid, Formic, estimation of, 627 
separation from acetic, 634 

— Gallic, 357, 366, 485, 693 

— Gallotannic, 695 

— Hippuric, 663 

— Hydracrylic, 644 

— Hydriodic, 950 
estimation of, 951 

— Hydrobromic, 950 

— Hydrochloric, 949 

— Hydrocyanic, 345 
estimation of, 345 

in oil of bitter almond, 346 

separation of, 345 

— Igasuric, 251, 700 

— Illurinic, 491, 495 

— Iodic, 953 

— Ipurolic, 385 

— Isatropic, 111 

— Jalapinolic, 387 

— Kino-tannic, 484 

— Lactic, 643 

estimation of, 645 

— Z-mandelic, 341 

— Margaric, 632 

— Meconic, 206 

— Melilotic, 691 

— Methylene Hippuric, 663 

— Myristic, 632 

— Nitroparaphenolsulphonic, 718 

— Nonylic, 632 

— Nucleic, 724, 895 

— Oleic, 941 

— Ophelic, 352 

— Orthosulphocarbolic, 718 

— Oxalic, 646 

— Palmitic, 632 

— Para-creosotic, 672 

— Pelargonic, 632 

— Perchloric, 953 

— Phenolsulphonic, 717 

— Phthalic, 665 

— Picric, 756 

— Piperonylic, 358 

— Polygalic, 329 

— Protocatechuic, 693 

— Quillaic, 328, 701 

— Quinic, 700 

— Rheinolic, 366-369 

— Salicylic, 370, 429, 436, 671 

estimation of, 674, 675, 676 

in aspirin, 687 



Acid, Formic, derivatives of, 677 

— Santoninic, 393 

— Sativic, 633 

— Sinapic, 348 

— Sozolic, 708 

— Stearic, 633 

— Strophanthic, 313 

— Succinic, 647 

— Sulphanilic, 717 

— Tannic, 695 

estimation of, 696 

— Tartaric, 648 
estimation of, 650 

— Taurocholic, 722 

— Tiglic, 275, 640 

— Trichloracetic, 593 

— Trichlorbutyric, 593 

— Tropic, 110, 670 

— Truxillic, 126 

— Valerianic, 447, 448, 631 
Acids, organic aliphatic, 624 

— acetic series, separation of, 637 
estimation of in admixture, 638 

— acrylic series, 639 
Aconite, Japanese, 264 

— species, 265 
Aconitin, 267 

— separation and estimation, 272 
Aconitum napellus, alkaloids of, 264 

— fisheri, 264 
Acetophenone, 605 
Actea alba, 339 

— rubra, 339 

— spicata, 339 
Adalin, 823 
Adenin, 296 
Adonis vernalis, 339 
Adlumidin, 248 
Adlumin, 248 

Adlumia cirrhosa, alkaloids of, 244 

Adonidin, 339 

Adrenalin, 827 

Agathin, 683, 808 

Agropyron repens, 415 

Airol, 994 

Albargin, 972 

Albaspidin, 398 

Alcohol, Anisyl, 554 

— Butyl, 542 

— Cinnamyl, 553 

— Cuminic, 553 

— determination, 2 



INDEX 



1053 



Alcohol Ethyl, 537 

, determination of in presence of 

methyl, 538, 540 

ether mixture, 539 

estimation of in presence of 

acid, 541 

— Methyl, 530 

estimation of, 535 

determination of in presence of ace- 
ton, 603 

— Ortho-oxybenzyl, 553 

— Propyl, 542 

— Salicyl, 553 
Alcohols, 529 

— general properties of monohydric, 530 

— identification of in oils, 935 
Alcoholometric tables, 3 
Aldehyde, Anisic, 456 

— Cinnamic, 459 

— estimation of by Burgess method, 932 

— identification and determination in 
oils, 931 

Aldehydes, 570 

— determination of, 586 
Aletris farinosa, 331 
Afridol, 980 

Alizarin, 528 
Alkaloids, definition, 71 

— estimation of, 78 

— Heikel's method, 79 

— microchemical examination, 76 

— separation and purification, 72 

— Solanum, distinguishing tests, 112 
AUyl isothiocyanate, 348 

Allspice, 457 

Aloes, 360 

Aloin, 362, 364 

Alpha-naphthol, 779 

Alphol, 682, 782 

Alphozone, 569 

Altingia excelsa, 714, 716 

Alstonia constricta, alkaloids of, 181 

Alstonin, 181 

Aluminol, 782 

Aluminium, 1013 

— beta-naphtholdisulphonate, 782 

— estimation of, 1013 

— hydrate, 1013 

— and potassium sulphate, 1013 

— silicate, 966, 1013 
Alypin, 145 
Ambrosia elatior, 396 



Aminoacetphenetidin, 867 
Aminophenols, 853 
Ammonia, 1025 

— estimation of in meat extract, 890 

spirit, 1029 

liniments, 1029 

Ammoniacum, 496 
Ammoniated mercury, 980 
Ammonium, 1025 

— bromide, 1026 

— carbonate, 1026 

— chloride, estimation of in antiseptic 

tablets, 985 
antiseptic tablets, 1025 

— citrate, 654 

— salts, estimation of, 1029 

— succinate, 647 
Amygdalin, 343 
Amygdophenin, 870 
Amyl bromide, 734 
Amyl iodide, 735 
Amylene, 735 
Amyl nitrite, 733 

assay, 734 

Amyloform, 578 
Amyl salicylate, 735 

— valerate, 735 
Anacardium occidentale, 700 
Analgen, 816 
Anaesthesin, 143 
Anapyralgin, 871 
Androsin, 324 
Anesthetics, synthetic, 137 
Angelica, 631, 640, 641 
Anilin, 831 

Anise, 455 

— ketone, 456 
Anisic aldehyde, 596 
Angostura bark, alkaloids of, 181 
Anhalamin, 308 

Anhalin, 307 
Anhalonidin, 307 
Anhalonium, assay, 27 

— fissuratum, alkaloids of, 307 
Anthraquinone, 528 

— drugs, 360 

identification of, 376 

Antiarin, 314 
Antiaris toxicaria, 314 
Antimony, 1000 

— and potassium tartrate, 1000 

— estimation of, 1001 



1054 



INDEX 



Antimony oxide, 1001 

— sulphide, 1001 

— sulphurated, 1000 
Antinosin, 667 
Antipyrin, 792 

— estimation of, 795 

in tablets with caffein, 801 

— iodide, 804 

— mandelate, 803 

— monobromide, 804 

— resorcylate, 804 

— salicylate, 803 

— salicylacetate, 804 

— separation of from acetanilid and sul- 

phonal, 800 

■ — acetphenetidin and codein, 797 

Antithermin, 791 
Apiol, 787, 935 

— dill, 419 
Apocodein, 204 
Apocynamirin, 324 
Apocynum, assay, 33 

— cannabinum, glucosides of, 324 

— androsaemifolium, glucosides of, 324 

— pubescens, glucosides of, 324 
Apomorphin, 202 
Arabinose, 617 

Aralia racemosa, 329 

— nudicaulis, 329 
Arbutin, 334, 335 
Arctium lappa, 451 

Areca catechu, alkaloids of, 89 

Arecaidin, 91 

Arecolin, 90 

Argentamin, 809, 975 

Argentol, 816 

Argonin, 973 

Argyrol, 896, 973 

Arhovin, 808 

Aristoehin, 175 

Aristolochia serpentaria, 406 

— reticulata, 406 
Arnica montana, 454, 640 
Arrhenal, 875 
Arsacetin, 876 

Arsenic, 997 

— compounds, organic, 873 

— detection and determination, 19 

— estimation of in presence of other 

metals, 999 

— peptonate, 882 

— tribromide, 998 



Arsenous oxide, 997, 998 

estimation of, 999 

Arsen-triferrin, 882 

Arsenoferratin, 881 

Arsenoferratose, 881 

Arsphenamine, 877 

Asarol, 786 

Asarum canadense, 406 

Ascaridole, 395 

Aseptol, 718 

Artemisia absinthium, 391, 394 

— cina, 391 

— maritima, 391 

— pontica, 392 

— species, 391 
Asafetida, 506 

— lead number of, 509 
Asarone, 419 

Ash, determination, 6 
Asclepias tuberosa, 437 

— species, 438 
Asparagin, 647 
Aspidinol, 398 
Aspidosamin, 180 
Aspidosperma, assay, 28 
Aspidosperma Quebracho-bianco bark, 

alkaloids of, 180 
Aspidospermatin, 180 
Aspidospermin, 180 
Aspirin, 680, 686 
Assays, crude drug, 23 

Lloyd procedure, 68 

Atophan, 817 

Atoxyl, 876 

Astragalus species, 467, 469 

Atisin, 270 

Atomic weights, 1033 

Atropa belladonna, alkaloids of, 100 

Atropamin, 110 

Atropin, 104 

— determination of in tablets, 114 
Atropurol, 434 

Atrocin, 109 



Balm of Gilead, 490 
Balsam, 481 

— Canada, 486, 489 

— Copaiba, 490 

— Gurjun, 495 

— Honduras, 713 

— Mecca, 490 



INDEX 



1055 



Balsam Peru, 705 

— , Tolu, 705 

Balsamodendron gileadense, 490 

— indicum, 505 

— kafal, 505 

Baptisia tinctoria, alkaloids of, 97 
Barium sulphide, 955 
Barosma betulina, 787 

— crenulata, 787 
Baumes, 702 
Bdellium, 505 
Beef peptone, 893 

— jelly, 893 

— iron and wine, 893 
Belladonna, assay, 28 

— plaster, assay, 115 
Benzacetin, 680 
Benzaldehyde, 594 

— cyanohydrin, 344 

— estimation of, 594 
Benzanilid, 852 
Benzoin, 702 
Benzoiin, 606 
Benzol, 520 
Benzophenone, 606 
Benzosalin, 683, 728 
Benzosol, 768 
Benzoyl ecgonin, 123 
Benzyl morphin, 206 
Benzylideneacetone, 604 
Berbamin, 234 
Berberin, 232 

Berberis aquifolium, alkaloids of, 228 
Beta-naphthol, 779 

benzoate, 782 

estimation of, 781 

hydroxytoluic acid, 692 

lactate, 784 

salicylate, 783 

Betol, 682, 783 
Betula lenta, 687 
Bile acids, 721 
Bicuculla canadensis, 237 
Bikhaconitin, 269 
Bismal, 994 
Bismuth, 992 

— betanaphtholate, 783, 993 

— estimation of, 995 

— electrolytic, 997 

— oxide, 993 

— oxyiodogallate, 99-± 

— salicylate, 672 



Bismuth, salts, estimation of in presence 
of mercury, 988 

— subcarbonate, 993 

— subgallate, 694 

— subnitrate, 993 

— tribromphenate, 757 
Bistort, 376 

Bitter tonic drugs, 348 
Black haw, 446 
Blood tonics, 327 
Bocconia frutescens, 244 

— cordata, alkaloids of, 244 
Borneol, 554 . 

— brom-valerate, 555 

— isovalerate, 555 
Bornyval, 555 

Brassica, glucosides of, 347 

— junicea, 347 

— niger, 347 
Brenzcain, 148, 769 
Bromal, 591, 757 

— hydrate, 591 
Bromalin, 595 
Bromamide, 832 
Brometone, 743 
Bromin, 946 
Bromoform, 743 
Bromural, 823 
Brovalol, 555 
Brucin, 256 
Bryonia alba, 448 

— dioica, 448 
Bryonol, 449 
Bryony root, 448 
Buckthorn, 373 
Buchu, 787 
Bulbocapnin, 238 
Burdock, 451 
Butternut root bark, 357 
Butyl-chloral, 591 
hydrate, 591 

Cactus, alkaloids of, 306 
Caffein, 287 

— estimation of in coffee, 290 

granular effervescent salt, 653 

tea, 289 

Calabar bean, alkaloids of, 302 
Calcium, 1019 

— carbonate, 1019 

— dibrombehenate, 634 

— eosolate, 771 



1056 



INDEX 



Calcium, estimation of, 1020 

— glycerophosphate, 750 

— guiacolmonosulphonate, 771 

— hypophosphite, 1019 

— hypochlorite, assay, 952 

— monoiodobehenate, 634 

— peroxide, 1019 

— phosphate, 1019 

— sulphide assay, 955 
Calendula officinalis, 454 
Calomel, 979 

— colloidal, 982 

— estimation of in tablets with santonin, 

394 

— separation of from bismuth subcarbon- 

ate, 988 
Calomelol, 982 
Camphor, 608 

— estimation of in spirit of camphor, 611 
tablets, 614 

— monobromated, 613 
Cannabinol, 422 
Canadin, 233, 432 
Cannabis sativa, 421 

assay, 30 

Cantharides, assay, 31, 412 

— plaster, assay of, 412 

— species, 411 

— tincture, assay of, 412 
Cantharidin, 411 
Capsaicin, 402 

Capsicum, estimation of pungency, 403 

— species, 401 
Carbohydrates, 616 

— estimation of in infant foods, 619 

— identification of, 617 
Carbon, 961 

Carbonates, estimation of, 962, 963 
Carbosant, 735 
Cardamon, 458 
Carica papaya, 901 
Carthamus tinctorius, 455 

detection of in saffron, 417 

Carum carvi, 456 
Carvacrol, 765 
Carvone, 456, 606 

— estimation of, 607, 608 
Caryophyllene, 458, 491 
Caryophyllus aromaticus, 457 
Cascara sagrada, 371 
Casein, 895 

Cashew nut, 700 



Cassia, 458 

— acutifolia, 370 

— angustifolia, 370 

— marilandica, 370 
Castoria, 370 
Catechol, 766 

Catecholmonoethylester, 774 
Caulophyllosaponin, 330 
Caulophyllum thalictroides, 330 
Caulosapogenin, 330 
Caulosaponin, 330 
Cephaelin, 225 

Cellulose, 617 

— estimation of, 622 
Cephselis acuminata, 223 

— ipecacuanha, 223 
Cerium, 1018 

— oxalate, 1018 

Cevadilla seed, alkaloids of, 274 

Cevadin, 275 

Cevin, 275 

Chamaelirium luteum, 331 

Charcoal, 961 

Chavicol, 785 

Chelidonium majus, alkaloids of, 244 

Chelerythrin, 246 

Chelidonin, 246 

Chenopodium ambrosioides, 395 

Cheronium opopanax, 505 

Cherry-laurel water, 344 

Chicle, 512 

Chimaphila umbellata, 334, 335 

Chinaphenin, 175 

Chinosol, 815 

Chiococca anguituga, 701 

Chirata, 351 

Chiratin, 352 

Cholin, 425, 450, 451 

Chondrodin, 306 

Chloral, 587 

— acetone chloroform, 592 
Chloralurethane, 591 
Chloralformamide, 591 

Chloral dimethyl-ethyl carbinol, 590 
Chloral hydrate, 586 

estimation of, 589 

Chloralimide, 592 
Chloralose, 592 
Chlorates, estimation of, 953 
Chloretone, 147 
Chlorine, 946 
Chloroform, 738 



INDEX 



1057 



Chloroform, estimation of, 742, 

Cholesterol, 917 

Chondrodendron tomentosum, alkaloids 

of, 305 
Chromium, 1012 

— estimation of, 1012 
Chrysarobin, 374 
Chrysoeridol, 441 
Cimicifuga racemosa, 339 
Cinchamidm, 155 
Cinchona, alkaloids of, 149 

estimation of, 170 

identification of, 167 

separation of, 174 

— assay, 33 

— barks, 150 
Cinchonamin, 155 
Cinchonicin, 167 
Cinchonidin, 154 
Cinchonin, 152 
Cinchotenin, 154 
Cinchotin, 155 
Cineol, 559 

— estimation of in oil of eucalyptus, 560, 

561 
Conium, assay, 38 
Cinnamein, 701, 702 
Cinnamene, 521 
Cinnamonum camphora, 608 

— cassia, 458 

— louriria, 458 

— zeylandicum, 458 
Cinnamylmetacresol, 761 
Citarin, 657 

Citral, estimation of, 586 
Citrullol, 354, 434 
Citrullus colocynthus, 353 
Claviceps purpurea, alkaloids of, 300 
Clemen's solution, 998 
Cloves, 457 
Cluytianol, 451 
Cocain, 119 

— cinnamyl, 121 

— separation and identification of, 128 
Coca, alkaloids of, 118 

— assay, 35 

— determination of alkaloids in, 138 

— identification of, 127 

— leaf constituents of, 136 
Cochlospermum gossypium, gum of, 470 
Cocillana bark, 426 

Cocoa butter, 935 



Cocculus indicus, 399 
Codamin, 196 
Codein, 191 

— colorimetric, estimation of, 216 

— estimation of in admixture with caffein 

acetanilid, acetphenetidin, and 
quinin, 218 

— estimation of in opium, 216 
Coffee, 284, 297 

— estimation of caffein in, 290 
Cohosh, blue, 330 

— black, 339 

— red, 339 
Colalin, 724 
Colchicin, 281 

— estimation in globules of and methyl- 

salicylate, 283 
Colchicein, 281 
Colchicum autumnale, 281 

— alkaloids of, 36 

— assay, 36 

Collinsonia canadensis, 442 
Colocynth, 353 

— identification of, 355 
Colophony, 488 

— in asafetida, 510 
Columbin, 235 
Commiphora africana, 505 

— species, 503 
Condimental drugs, 455 
Conhydrin, 85 
Conicein, 85 

Coniin, 83 

— estimation of, 86 
Coniferin, 414 
Coniferyl alcohol, 414 
Conium, assay, 38 

— detection of in anise, 455 
Conium maculatum, alkaloids of, 82 
Conquinamin, 165 

Convallaria assay, 33 

— majalis, 322 
Convallamarin, 322 

— glucosides of, 322 
Convallarin, 322 
Convolvulinolic acid, 385 
Convolvulus scammonia, 382 
Copaiba, 490 

— African, 495 

— detection of, 496 

— Maracaibo, 491 

— Maranham, 491 



1058 



INDEX 



Copaiba, Para, 491 
Copper, 989 

— estimation of, 989, 991 
Coriander, 457 
Coriandrum sativum, 457 
Corycavamin, 238 
Corybulbin, 238 
Corycavin, 238 
Corydalin, 238 
Corydalis canadensis, 237 
— ■ cava, alkaloids of, 237 
Corydin, 238 

Coryfin, 558 

Corytuberin, 238 

Cosaprin, 717 

Coto bark, 358 

Cotoin, 358 

Cotton root bark, 436 

Cough remedies, 340 

Coumarin, 691 

Cramp bark, 446 

Creatin, estimation of in meat extract, 891 

Creatinin, estimation of, 892 

Creosol, 773 

Creosotal, 772 

Creosote, 772 

— carbonate, 772 

— oleate, 772 

— phosphate, 772 

— phosphite, 772 

— tannate, 772 

— valerate, 772 
Cresalols, 761 
Cresatin, 761 
Cresols, 758 

— estimation of, 758 
Crocus sativus, 416 
Crurin, 814 
Cryptopin, 198 
Cubeb, 419 
Cubebin, 420 
Culver's root, 443 
Cuminic aldehyde, 597 
Cuprein, 165 
Cuprol, 725 

Curare, alkaloids of, 250 

Cusco bark, alkaloids of, 166 

Cuscohydrin, 124 

Cusparia officinalis bark, alkaloids of, 181 

Cusparidin, 181 

Cusparin, 181 

Cyanogenetic glucosides, 340, 467 



Cycloform, 145 

Cymene, 521 

Cynoctonin, 270 

Cynotoxine, 324 

Cytisin, 97 

Cytisus laburnum, alkaloids of, 97 

— scoparius, alkaloids of, 94 

Damiana, 436 

— detection of in tonics, 437 
Dandelion root, 450 

Datura stramonium, alkaloids of, 100 

Delphinin, 98 

Delphinium staphisagria, alkaloids of, 98 

— consolida, alkaloids of, 98 
Delphinoidin, 98 
Delphisin, 98 

Dermatol, 694 
Dextrin, 617 

— estimation of in infant foods, 619 
Dextrose, 617 

— estimation of in infant foods, 619 
Diacetyl morphin, 204 
Diacetylparamidophenol, 871 
Diacetyltannin, 697 
Diaphtherin, 817 

Diaphtoi, 817 

Diaspirin, 680 

Diastase, 907 

Diathesin, 553 

Dicentrin, 238 

Dicinchonicin, 167 

Diethylenediamine, 809 

Diethylsulphonediethylmethane, 747 

Diethylsulphonedimethylmethane , 746 

Diethylsulphonemethylethylmethane, 747 

Digestives, 896 

Digitalein, 320 

Digitalin, 317 

— commercial, 320 
Digitalis, assay, 39 

— examination of tincture by Martin- 

dale's method, 321 

— purpurea, glucosides of, 315 

— tests for, 321 
Digitaligenin, 318 
Digitalose, 318 
Digitonin, 318 
Digitoxigenin, 317 
Digitoxin, 316 

— determination, 42 
Digitoxose, 317 



INDEX 



1059 



Diiodobetanaphthol, 784 

Diiodoform, 745 

Diiodoparaphenol sulphonic acid, 719 

Diisobutylcresol iodide, 760 

Dimethylacetal, 735 

Dimethylaminotetraminoarsenobenzene, 

881 
Dimethylhomocatechol, 773 
Dimethyl piperazine, 810 

tartrate, 810 

Diosphenol, 787 

— detection of, 789 
Diphyllin, 247 
Diquinicin, 167 
Dionin, 205 

Diorthocumarketone, 605 
Dita bark, alkaloids of, 181 
Dithion, 679 

Dock, yellow, 375 

— bitter, 375 

Dorema ammoniacum, 496 
Dormiol, 590 

Dryobalanops camphora, 554 
Dryopteris filix-mas, 397 

— marginalis, 397 

Duboisia Hopwoodii, alkaloids of, 99 

— myoporoides, alkaloids of, 100 
Dulcin, 665, 871 

Duotol, 768 
Dutch liquid, 731 

Ecballium elaterium, 352 

Ecgonin, 125 

Echinacea angustifolia, 454 

— pallida, 454 

— purpurea, 454 
Elarson, 883 
Elaterin, 352 
Electromercurol, 981 
Elatteria cardamomum, 458 
Embelia ribes, 701 
Emetin, 225 
Emmenagogue pills, 338 
Emodin, 367, 368, 373 

— aloe, 362, 363 

— monomethyl ether, 366, 367, 368 
Empyroform, 580 

Emulsion, estimation of oil in, 922 
Enesol, 883 
Eosote, 772 
Epicarin, 692 
Epinephrin, 827 



Epinephrin, estimation of, 829 
Ergot, alkaloids of, 300 

— assay, 43 
Ergotinin, 301 
Ergotoxin, 301 
Ergoxanthein, 302 
Eriodictyol, 440 
Eriodictyon californicum, 438 
Eriodonol, 441 
Erystamine, 585 

Erythrol tetranitrate, 738 

Eschscholtzia californica, alkaloids of, 244 

Eseramin, 304 

Eserolin, 304 

Estoral, 558 

Ether, 562 

— determination of alcohol and water in, 

567 

— estimation of in alcohol mixture, 539 
Ethereal salts, 727 

Ethyl acetate, 732 

— benzoate, 733 

— bromide, 730 

— carbolate, 758 

— carbonate, 824 

— chloride, 729 

— cinnamate, 733 

— diiodosalicylate, 733 

— formate, 733 

— iodide, 731 
— - lactate, 731 

— morphin, 204 

— nitrite, 732 

— valerate, 733 
Ethylenediamine, 808 
Ethylene dibromide, 732 

— dichloride, 731 
Ethylenetetraiodide, 745 
Ethylidene chloride, 731 
Ethylmercaptan, 746 
Ethylthiocarbimide, 733 
Eucain alpha, 138 

— beta, 138 
Eucalyptol, 559 
Eucalyptus rostrata, 484 
Eucodein, 204 
Eudoxin, 667 
Eugallol, 778 
Eugenoform, 786 
Eugenol, 457, 458, 785 

— benzoate, 786 

— cinnamate. 786 



1060 



INDEX 



Euguform, 771 
Euonymol, 434 
Euonymus americanus, 433 

— atropurpureus, 433 
Euonysterol, 434 
Eupatorin, 410 
Eupatorium glutinosum, 48 

— rebaudianum, 410 
Euphorbia pilulifera, 432 
Euphorin, 823 
Eupthalmin, 140 
Eupyrin, 870 
Euquinin, 175 
Euresol, 775 

Eurobin, 375 

Europhen, 760 

Euscopol, 112 

Erythroxylon coca, alkaloids of, 118 

Exalgin, 851 

Exogonium purga, 382 

Extract, codliver, 894 

— Goulard's assay of, 977 

— malt, 911 

— meat, 887 

analysis of, 887 

estimation of glycerin in, 548 

Fabiana imbricata, 441 

Ferro sajodin, 634 

Female remedies, 330 

Feminella, 417 

Fenchone, 456, 615 

Fennel, 456 

Ferratin, 1010 

Ferrinol, 725 

Ferrous carbonate assay, 1004 

— hypophosphite, 1009 

— salts, estimation of iron in, 1007 
Ferropyrin, 803 

Ferula asafetida, 506 

— fetida, 506 

— rubricaulis, 506 

— sumbul, 435 

Fiber crude, estimation of, 622 
Fibrolysin, 824 
Filicin, 397 
Filmaron, 398 
Fish berry, 399 
Flavaspidic acid, 398 
Flavaspidin, 398 
Fluorescein, 775 
Fluoroform, 743 



Fceniculum vulgare, 456 
Formaldehyde, 572 

— acetamide, 579 

— acetate, 578 

— estimation of, 573, 574 
Formaloin, 579 
Forman, 558, 579 
Formanilid, 852 
Formicin, 579 
Formopyrin, 580, 804 
Formylphenetidin, 868 
Fortoin, 359, 579 
Fowler's solution, 998 

assay of, 999 

Francois reagent. 740 
Fraxinus ornus, 550 

Fumaria officinalis, alkaloids of, 244 

Galactochloral, 592 
Galactose, 617 
Galbanum, 498 
Galipidin, 181 
Galipin, 181 
Galipoidin, 181 
Gallanilide, 695, 852 
Gallanol, 695, 852 
Gallicin, 695, 728 
Gallobromol, 695 
Galloformin, 695 
Gallogen, 694 
Gamboge, 499 
Garcinia morella, 499 
Gaultheria leucoceupa, 687 

— procumbens, 687 

— punctata, 687 
Geissospermin, 182 

Geissospermum vellosi, alkaloids of, 182 
Gelsemin, 240 

Gelsemium, assay, 45 

Gelsemium sempervirens, alkaloids of, 239 

— alkaloids, separation of, 242 
Geneserin, 305 

Genesta tinctoria, alkaloids of, 97 
Gigartina mamillosa, 466 
Ginger, 404 

— wild, 406 
Ginseng, 330 
Gitalin, 319 
Gentiamarin, 349, 350 
Gentiana Elliotii, 349 

— lutea, 348 

Gentian root, glucosides of, 348 



INDEX 



1061 



Gentiin, 349, 351 
Gentiopicrin, 349, 350 

— separation of, 351 
Gitonin, 320 
Glaucin, 238, 248 

Glaucinum corniculatum, alkaloids of, 244 
Glucose, commercial determination, 18 
Glucosides, 309 

— reactions of, 310 
Glutei, 578 
Glycerin, 542 

— affect on alcohol determination, 2 
• — estimation of, 548 

in meat juices and extracts, 548 

pharmaceutical preparations, 

549 

— identification of, 545 
Glycerophosphates, 748 

— estimation of, 961 
Glycerophosphoric acid, 748 
Glycocholic acid, 642, 722 
Glycosal, 681 
Glycothymoline, 556 
Glycyrrhiza glabra, 407 

— glandulifera, 407 
Gold, 991 

— and sodium chloride, 992 

— estimation of in medicines, 992 
Gnoscopin, 200 

Goa powder, 374 

Granular effervescent salt, analysis of, 653 

estimation of carbonate in, 963 

Grindelia species, 452 
Grindelol, 453 
Griserin, 816 
Guacamphol, 769 
Guaethol, 774 
Guaiacum officinale, 482 

— sanctum, 482 
Guaiamar, 769 
Guaiacol, 767 

— benzoate, 768 

— benzyl-ester, 769 

— camphorate, 769 

— carbonate, 768 

— cinnamate, 769 

— glyceryl-ether, 769 

— methyl-glycolate, 770 
— ■ phosphate, 770 

— phosphite, 770 

— salicylate, 770 

— valerate, 770 



Guaiaquin, 177 
Guaiaquinol, 177 
Guaiasanol, 148 
Guaicyl, 148 
Guanin, 296 
Guarana, assay, 46 
Guarea rusbii, 426 
Gum acacia, 463 

— arabic, 463 

determination of, 464 

— cauchillo, 513 

— chewing, 512 , 

— indian, 469 

— mesquite, 465 

— quince seed, 466 

— red, 484 

— Senegal, 463 

— tragacanth, 467 

determination of, 468 

Gum plant, 452 
Gums, 460 

— characteristics of, 462 

— classification of, 461 
Guvacin, 91 

Gymnosporia, manna-like incrustation on, 

552 
Gynoval, 555 

Halogen acids, 949 

estimation of, 951 

oxyacids, 952 

Halogens, identification and determina- 
tion, 945, 946 
Hamamelis virginiana, 428 
Hardwickia manii, 490 

— pimenta, 490 
Harmalin, 263 
Harmalol, 263 
Harmin, 263 

Headache mixtures, assay of, 795, 797 

Heart tonic drugs, 311 

Hedeoma pulegioides, 615 

Hediosit, 618 

Hedonal, 824 

Hegonon, 973 

Heliotropin, 599 

Helleborein, 338, 339 

Helleborin, 338 

Helleborus niger, glucosides of, 338 

Helmitol, 584 

Helonias, 331 

Hemaboloids, 1010 



1062 



INDEX 



Hemogallol, 1011 
Henna, 371 
Heroin, 204 

— separation of from codein and morphin, 

220 

morphin, 220 

Hetacresol, 761 
Hetralin, 583, 776 
Hexal, 583 
Hexamethylenetetramine, 580 

— bromethylate, 585 

— citrate, 584 

— estimation of, 581 
in tablets, 581 

granular effervescent salt, 653 

— oxymethylsulphonate, 585 

— resorcinol, 583 

— salicylate, 584 

— salicyl sulphonic acid, 583 
Hippol, 663 

Histosan, 771 
Hoang-Nan, 251 

assay, 46 

Holocain, 141 
Homatropin, 112 
Homocatecholmethylester, 773 
Homochelidonin, 244, 247 
Homoeriodictyol, 440 
Homoeuonysterol, 434 
Homosaligenin, 787 
Homotaraxasterol, 450 
Hops, 424 
Humulol, 425 
Humulus lupulus, 424 
Hydrangea arborescens, 427 
Hydrargryol, 718 
Hydrastin, 230 

— separation from berberin, 236 
Hydrastinin, 231 

Hydrastis canadensis, alkaloids of, 228 
Hydrastis, assay, 46 
Hydrazine, 791 
Hygrin, 124 
Hydrocarbons, 518 

— cyclic, 521 

— determination of, 519 
Hydrocotoin, 358 
Hydrocotarnin, 200 
Hydrogen sulphide, 955 
Hydro-quebrachin, 180 
Hydroquinidin, 164 
Hydroquinin, 164 



Hydroquinone, 776 
Hydroxyhydroquinone, 779 
Hydroxyquinolin, 815 
Hyoscin, 100 
Hyoscyamin, 108 
Hyoscyamus assay, 48 
Hyoscyamus niger, alkaloids of, 100 
Hypnal, 592, 805 
Hypnoacetin, 870 
Hypnone, 605 
Hypophosphites, 961 
Hypoxanthin, 295 

Ichthoform, 580 
Ichthyol compounds, 719 
Ignatia, 251 

— assay, 46 

Imperatoria ostruthium, 265 
Incarnatrin, 431 
Indaconitin, 269 

Infant foods, analysis of, 619 
Inulin, 450, 452, 617 
Iodanisol, 745 
Iodides, estimation of, 951 
lodin, 945 

— estimation of, 947, 949 

in ointment, 948 

organic compounds, 954 

— peroxide, 953 
Iodoform, 743 

— estimation of, 744 
Iodoformal, 585 
Iodoformin, 585 
Iodol, 812 
Iodolin, 815 

Iodomethylphenylpyrazolon, 806 
iodone, 667 

Iodophen, 667 

Iodylin, 679 

Iothion, 745 

Ipecac, alkaloids of, 222 

— assay, 48 

— wild and false, 223 
Ipomcea orizabensis, 382, 386 

— purga, 382 

— purpurea, 382 

— turpethum, 388 
Ipuranol, 341, 386, 416 
Ipurganol, 384 

Iris florentina, 415 

— versicolor, 415 
Irish moss, 466 



INDEX 



1063 



Iron, 1003 

— assay of in iron and quinin citrate, 1006 
strychnin citrate, 1006 

— estimation of, 1004, 1005, 1007 

— organic compounds of, 1009 

— peptonate and manganese, 1009 

— peptonate, 1012 

— reduced, assay, 1001 

— salts, estimation of iron in, 1005 
isocorybulbin, 238 

Isoborneol isovalerate, 555 
Isopilocarpin, 93 
Isopral, 743 
Isotrifolin, 430 

Jaborandi, alkaloids of, 91 
Jalap, 383 

— assay, 49 

— resin, examination of, 388 
James's powder, 1001 
Japaconitin, 268 

Jervin, 278 

Jesaconitin, 269 

Jeteorrhiza calumba, alkaloids of, 229 

Juglans cineraria, 357 

Juniper communis, 789 

Kaempferol, 370 

Kalmia latifolia, 335 

Kelene, 729 

Ketones, general reactions, 599 

— identification and determination in 

oils, 933 
Kidney remedies, 788 
Kola, analysis of, 298 

— assay, 49 
Kolatin, 298, 299 
Kamala, 433 
Krameria species, 427 
Kresamine, 809 
Kryofine, 867 

Lactophenin, 868 
Lactose, 617 

— estimation of in infant foods, 619 
Lactucarium. 501 

Lactuca sativa, 502 

— virosa, 501 
Lactucerol, 502 
Lactucin, 502 
Lactucerin, 502 
Lanthopin, 197 



! Lapaconitin, 270 

Largin, 975 
J Larix decidua, 486 
I Laudanidin, 196 

Laudanin, 195 

Laudanosin, 196 

Lead, 975 

— acetate, 630, 975 

— estimation of, 936 

in Goulard's extract, 977 

— monoxide, 975 

— nitrate, 975 

— oleate, 641, 975 

— subacetate, 875 

— sulphite, 975 

— sulphocarbolate, 975 
Lenirobin, 375 
Lenigallol, 778 
Leontin, 331 
Leptandra, 443 
Levulose, 617 
Licorice, 407 

— assay, 49 

— paste, analysis of, 408 

— powder, compound, 410 
Limonene, 456 
Liquidambar orientalis, 713 

— styraciflua, 713 
Listerine, 556 
Lithium, 1025 

— carbonate, 1025 

— citrate, 1025 

— estimation of, 1026, 1027, 1028 
Lobelia, assay, 50 

— inflata, alkaloids of, 96 
Lobelin, 96 

Lophophora alkaloids of, 307 

— Williamsii, 307 

— lewinii, 307 
Lophophorin, 308 
Loretin, 816 
Losophan, 761 
Luminal, 827 
Lupetazin, 810 
Lupulin, 424 
Lyaconitin, 269 
Lycetol, 810 
Lysidine, 810 

Macrotys, 339 
Magnesium, 1021 

— estimation of, 1022 



1064 



INDEX 



Magnesium, salts of, 1021 
Malakin, 869 
Malarin, 870 
Malefern, 397 

— assay of extract, 397 
Mallotus phillipinensis, 433 
Maltol, 777 

Maltose, 617 

— estimation of in infant foods, 619 
Malubrin, 806 
/-mandelonitrile glucoside, 341 

— separation of, 342 

Mandragora officinarum, alkaloids of, 100 
Mandrake, 380 
Manganese, 1014 

— dioxide, 1014 

— estimation of, 1014, 1015 

— iodide, 1014 
Manna, 551 
Mannitol, 550 
Maretin, 824 
Marigold, 455 
Martius yellow, 780 
Matieo, 418 
Meconidin, 196 
Mentha pulegium, 615 
Menthol, 556 

— estimation of in oil of peppermint, 557 
Menthone, 616 

Menthyl chlormethyl ester, 558 

— ethylgycolate, 558 

— valerianate, 558 
Mercaptans, 745 
Mercuric bromide, 979 

— chloride, 979 

— cyanide, 979 

— iodide, 979 

— nitrate, 979 
Mercurol, 726, 980 
Mercurous chloride, 979 

— iodide, 980 
Mercury, 978 

— and chalk, 978 

— estimation of electrolytically, 983, 984 

in ointments, 986 

salts, 982 

organic compounds, 988 

soaps, 982 

surgical dressings, 988 

tablets, 984 

— separation of from other metals, 988 

— oxides, 978 



Mercury, paraphenolsulphonate, 718 

— salicyl arsenate, 883 
Mescale, assay, 27 

— button, 307 
Mescalin, 307 
Mesotan, 681 
Methacetin, 854 
Methoxyacetphenetidin, 867 
Methylacetanilid, 851 

— acetphenetidin, 867 

— acetyl salicylate, 728 

— aesculin, 343 

— benzoyl salicylate, 728 

— chavicol, 785 

— chloride, 727 

— coniin, 85 

— cytisin, 330 

— eugenol, 786 

— gallate, 695, 728 

— heptenone, 605 

— hydrocotoin, 358 

— iodide, 728 

protocotoin, 358 

— salicylate, 329, 681, 687 

— assay of, 689 
/3-Methyl-sesculetin, 341, 384 
Methylal, 578, 728 
Methylenedimethyl ester, 728 
Methylene blue, 820 

— creosote, 772 

— diacetate, 578 

— diantipyrin, 804 

— dichloride, 729 

— dicotoin, 729 
Mitchella repens, 444 
Microcidin, 784 

Monochlorethylene chloride, 731 
Monotal, 770 

Moringa oleifera, 633 
Morphin, 187 

— colorimetric estimation of, 216 

— estimation of in admixture with caffein, 

acetanilid, acetphenetidin and quinin, 
218 

— estimation of in Chinese pills, 215 

laudanum, 213 

paregoric, 211, 214 

powdered opium, 211 

syrups, 211 

tablets, 214 

Morphinmethylbromide, 191 
Mother's cordials, 340 



INDEX 



1065 



Mustard plaster, 347 
Mustard seed, 347 

assay, 51 

Mydrol, 806 
Myoctonin, 270 
Myrrh, bisabol, 504, 505 

— herabol, 503 

Nandinin, 234 
Nan-ta-yok, 715 
Nargol, 726, 975 
Naphthalene, 529 
Narcein, 201 
Narcotin, 198 
Neoarsphenamine, 878 
Neosalvarsan, 878 
Neurodin, 825 
Neuronal, 821 
Nickel, 1002 

— bromide, 1002 

— estimation of, 1002 
Nitrates, estimation of, 945 

in meat extracts, 892 

Nitrites, estimation of, 945 
Nirvanin, 145 

Nitrogen, 945 

— estimation of, 888 
Nitroglycerin, 736 
Nitroglucose, 738 

Non-volatile material, determination, 6 

Nosophen, 667 

Novargan, 974 

Novaspirin, 680 

Novatophan, 817 

Novocain, 146 

Nuclein, 724 

Nucleoproteins, 895 

Nux Vomica, alkaloids of, 250 

assay, 51 

Oil, anise, 928, 453 

— apricot kernel, 923 

— asafetida, 507 

— ben, 623 

— birch, 688 

— bitter almond, 346 

estimation of benzaldehyde in, 

594 

— caraway, 456, 930 

— castor, 922 

— cassia, estimation of cinnamic aldehyde 

in, 596 



Oil, chaulmoogra, 924 

— Cinnamonum species, 459 

— clove, 457 

— codliver, 919 

— copaiba, 494 

— coriander, 930 

— cotton seed, 924 
Halphen test, 915 

— croton, 640, 923 

— cubeb, 421 

— estimation of unsaponifiable matter, 519 

— eucalyptus, estimation of cineol in, 

560, 561 

— fennel, 456, 929 . 

— gaultheria, 688 

— grindelia, 453 

— haarlem, 488 

— juniper berries, 798 

— myrbane, 520 

— nutmeg, 632 

— olive, 922 

— origanum vulgare, 766 

— palm, 632 

— peanut, 915, 933 

— pennyroyal, 615 

— peppermint, estimation of menthol in, 

557 

— pimento, 457 

— Roman camomile, 553 

— rue, 632 

— sandal-wood, 930 

— savin, 935 

— sesame, 924 

Baudoin test, 917 

Villavecchia test, 917 

— star anise, 928 

— sweet almond, 923 

— tansy, 615 

— theobroma, 925 

— thuja, 615 

— turpentine, 486 

— valerian, 448 

— winter green, 688 
Oils, fixed, 913 

general methods for examination, 

913 

— volatile, 925 

general methods for examination, 

925 

identification of in preparations, 931 

Opium, 183 

— alkaloids of, 183 



1066 



INDEX 



Opium, alkoloids of, identification and 
determination, 207 

— assay, 53 

— tincture of, assay, 59 
Opopanax, 505 
Orcinol, 776 
Orexine, 818 

Orizaba root, 386 
Orthoform, 143 
Orthoformic ether, 733 
Ouabain, 314 
Ovaferrin, 1010 
Oxaphor, 612 
Oxyacanthin, 234 
Oxgall, 721, 723 
Oxygen, 940 
Oxynarcotin, 200 
Oxyphenybenzylketone, 606 

Padus virginiana, 340 
Palmatisin, 270 
Pancreatin, 902 

— determination of milk curdling prop- 

erties, 905 

— estimation of, 903 
Pankreon, 699 
Papain, 901 

Para coto, 358 

Paracotoin, 358 

Paraiodanilin, 832 

Paraiodophenol, 758 

Parthenium integrifolium, 454 

Paratophan, 817 

Papaveramin, 195 

Papaverin, 193 

Paraformaldehyde, 575 

Parahydroxyphenylethylamin, 301 

Paratolyldimethylpyrazole, 805 

Pareira brava, 305 

Parillin, 327 

Pearson's solution, 998 

Peganum hamala, alkaloids of, 263 

Pelletierin, 117 

Pellotin, 308 

Pennyroyal, 615 

Pepsin, 896 

— determination of in chewing gum, 513 

proteolytic activity, 897 

Petrolatum, 518 

Peucedanum galbanifluum, 498 

— rubricaule, 498 
Pepper, oleoresin of, 88 



Perborates, 968 

— estimation of, 969 
Permanganates, assay of, 1016 
Peronin, 206 

Peroxide, assay of metallic, 944 

— benzoylacetyl, 569 

— hydrogen, 941 

— identification of in cold creams, etc, 

944 

— succinic, 569 
Phenacetin, 854 
Phenetidin salicylacetate, 869 
Phenocoll, 867 
Phenolphthalein, 666 

— separation from anthraquinone drugs, 

378 
Phenols, 753 

— identification and determination in 

oils, 932 
Phenosal, 869 
Phenyl-coumarin, 358 
--- hydrazine, 791 

— salicylate, 682, 683 

— urethane, 824 
Phenylenediamine, 819 
Phesin, 868 
Phloroglucinol, 778 
Phosphates, estimation of, 960 
Phosphoproteins, 895 
Phosphorus, 956 

— estimation of, 957 

in galenicals, 958 

rat paste, 957 

Phosphotal, 772 
Physostigma, assay, 60 

— venenosum, alkaloids of, 302 
Physostigmin, 303, 305 
Physovenin, 304 
Phytolacca, abyssinica, 427 

— decandra, 426 
Phytosterol, 917 
Pichi, 441 
Picradonidin, 339 
Picraena excelsa, 356 
Picrasmin, 357 
Picratol, 757 
Picrol, 775 
Picropodophillin, 381 
Picrotin, 400 
Picrotoxin, 399 
Picrotoxinin, 400 
Pilocarpidin, 93 



INDEX 



1067 



Pilocarpin, 92 

Pilocarpus, alkaloids of, 91 

— assay, 60 
Pimento officinalis, 457 
Pimpinella anisum, 455 
Pinene, 486 

— hydrochloride, 608 
Pinus echinata, 486 

— heterophylla, 486 

— palustris, 486 

— strobus, 414 

— sylvestris, 486 

— taeda, 486 
Piperazine, 809 

— quinate, 810 
Piperidin, 88 
Piperin, 87 
Piper cubeba, 419 

— species, 418 
Piperonal, 599 
Pipsissewa, 334, 335 
Pistacia terebinthus, 486 
Piturin, 99 

Plasters, types of, 515 
Pleurisy root, 438 
Pneumin, 772 
Podophyllin, 380 
Podophyllum emodi, 381 

— peltaltum, 380 
Podophyllotoxin, 381 

— estimation of, 382 
Poke weed, 426 
Pollantin, 396 
Polychloral, 591 
Polygala senega, 328, 687 
Pomegranate bark, assay, 61 

alkaloids of, 116 

Populin, 336, 338 
Populus alba, 336 

— candicans, 336 

— tremuloides, 336 
Porphyrin, 181 
Potassium acetate, 1023 

— antimonyl tartrate, 649 

— bichromate, 1012, 1024 

— bitartrate, 648, 1024 

— bromide, 1024 

— carbonate, 1024 

— chlorate, 953, 1024 

— diiodoresorcinol monosulphonate, 775 

— estimation of, 1026, 1027, 1028 

— guaia^ol-sulphonate, 771 



Potassium hypophosphite, 1024 

— iodide, 1024 

— nitrate, 1023 

— and sodium tartrate, 1025 
Pratensol, 430 

Pratol, 429 

Prickly ash, 431 

Proferrin, 1011 

Propazin, 143 

Proponal, 826 

Protan, 697 

Protargol, 974 

Protein, estimation of, 889 

Proteins, 884 

Protocotoin, 358 

Protopin, 197 

Protosal, 681 

Protoveratridin, 279 

Protoveratrin, 279 

Prulauresin, 341, 343 

Prunus lauro-cerasus, 341, 344 

— serotina, 340 
Pseudaconitin, 269 
Pseudocinchona africana, 180 
Pseudoconhydrin, 86 
Pseudojervin, 279 
Pseudomorphin, 192 
Pseudopelletierin, 117 
Psychotrin, 226 
Pterocarpus marsupium, 484 
Pulegone, 615 

Pumpkin seed, 450 

Punica granatum, alkaloids of, 116 

Purpurin, 529 

Pyoktanin blue, 853 

— yellow, 853 
Pyramidon, 794, 806 

— acid camphorate, 807 

— neutral camphorate, 807 

— salicylate, 808 
Pyrantin, 871 
Pyridin, 811 
Pyrogallol, 777 
Pyrrole, 812 

Quassia, 356 
Quassin, 356 
Quebrachamin, 180 
Quebrachin, 180 
Quercetin, 381, 429 
Quillaja saponaria, 328 
Quinamin, 165 



1068 



INDEX 



Quinaphthol, 177 
Quince seed, 467 
Quinicin, 167 
Quinidin, 164 
Quinin, 165 

— eosolate, 177 

— ethyl sulphate, 177 

— lygosinate, 176 

— phytin, 176 

— separation from belladonna, alkaloids, 

172 

— salts of, 159 
Quinoidin, 167, 815 
Quinolin, 813 

— bismuth sulphocyanate, 814 

— chloridomethylchloride, 815 

Rat powder, estimation of arsenic in, 999 

— paste, estimation of phosphorus in, 957 
Reagent, Froehde's, 1044 

— Hager's, 1044 

— Mandelin's, 1042 

— Marine's, 1044 

— Marquis', 1043 

— Mayer's, 1044 

— Millon's, 1044 

— Scheibler's, 1044 

— Sonnenschein's, 1044 

— Wagner's, 1043 
Rebaudin, 410 
Red clover, 428 
Remijia alkaloids, 165 
Resaldol, 776 
Resalgin, 804 
Resopyrin, 805 
Resorcinoform, 580 
Resorcinol, 774 

— hexamethylenetetramin, 776 

— monoacetate, 775 

— phthalein, 775 

— salol, 776 
Rhamnus californica, 372 

— carniolica, 373 

— cathartica, 373 

— frangula, 373 

— purshiana, 371 
Rhatany, 427 
Rhein, 366, 367, 368 

Resin, acids, separation of from fatty, 480 

— guaiacum, 482 

— kino, 484 

— thapsia, 485 



Resins, 460, 481 

— - acetyl value, estimation, 479 

— analysis of, 474 

— carbonyl value, estimation, 479 

— classification of, 471 

— constituents of, 471 

— ester value, estimation, 477 

— gum, 481 

— methoxyl value, 479 

— oleo, 481 
Rheum officinale, 365 

— palmatum, 365 

— raponticum, 365 
Rhubarb, 365 

— assay, 62 
Rochelle salt, 649 
Rubber, 511 
Rubijervin, 278 
Rumex acetosella, 375 

— crispus, 375 

— obtusifolius, 375 

Sabadilla seed, alkaloids of, 274 

assay, 63 

Sabadillin, 276 
Sabadin, 276 
Sabadinin, 276 
Sabal serrulata, 415 
Sabinol, 935 
Saffron, 416 

— American, 455 
Sabromin, 633 
Saccharin, 664 
Safrol, 785, 935 
Sagapenum, 510 
Sajodin, 634 
Salacetol, 604 
Salicin, 336 
Salicylamide, 821 
Salicylparaphenetidin, 869 
Salifebrin, 851 
Saligallol, 778 
Saligenin, 553, 787 
Salicylic aldehyde, 596 
Saliformin, 584 
Salitannol, 683 
Salithymol, 682 

Salix alba, 336 

— nigra, 336 
Salol, 682, 683 
Salophen, 682, 685 
Saloquinin, 175 



INDEX 



1069 



Salvarsan, 877 

— estimation of arsenic in, 879 
Sambucus nigra, 341 
Sambunigrin, 341, 343 
Sanguinaria, assay, 63 

— canadensis, 244 
Sanatogen, 895 
Sanguinarin, 245 
Sanoform, 679, 681 
Santalyl carbonate, 735 
Santonica, 392 

— assay, 64 
Santonin, 392 

— estimation of in tablets, 394 

santonica, 64 

Santyl, 681 

Saponaria officinalis, 329 
Saponins, 325 

— estimation of in emulsions, 334 

— reactions of, 325, 332 

— separation and identification of, 332 
Sarcin, 295 

Sarsaparilla, glucosides of, 327 

— species, 326 

— wild, 329 
Sarsasaponin, 327 
Saw palmetto, 315 
Scammony, 385 

— resin, examination, 388 
Scilla maritima, 323 
Sclererythrin, 302 
Scopolamin, 109 
Scopoletin, 241, 386 

Scopolia atropoides, alkaloids of, 100 
Scopolin, 111 
Scullcap, 442 
Scutellarein, 443 
Scutellaria altissima, 443 

— lateriflora, 442 
Sedatin, 870 
Sedative mixtures, 448 
Seidlitz mixture, 648 
Selenopyrin, 806 
Semperviren, 241 
Senecio aureus, 445 
Senega snake-root, 328 
Senegin, 329 

Senna, 370 

— estimation of in compound licorice 

powder, 410 
Septentrionalin, 270 
Serpentaria, 406 



Seven barks, 427 
Sidonal, 810 

Silicates, estimation of, 965 
Silver, 970 

— colloidal, 972 

— eosolate, 771 

— estimation of, 971 

— nitrate, 970 
Simaruba officinalis, 357 
Sinalbin, 347 
Sinapin, 348 

Sinapis alba seed, glucosides of, 347 
Sinigrin, 348 
Smilasaponin, 327 
Smilax medica, 326 

— officinalis, 326 

— ornata, 326 

— papyracea, 326 
Snake root, black, 340 

Canada, 406 

Virginia, 406 

Soap, 634 

— assay of, 646 

— bark, 326 

— liniment, assay of, 636 
Soap wort, 329 
Sodium, 1022 

— acid sulphanilate, 717 

— anhydromethylene citrate, 657 

— arsenoferri albuminate, 881 

— arsenate, 875 

— benzoate, 659 

— betanaphtholate, 784 

— bicarbonate, 1022, 1023 

— bromide, 1022 

— cacodylate, 874 

— chloride, 1022 

— estimation of, 1026, 1027 

— ferrialbuminate, 1010 

— glycerophosphate, 751 

— hypophosphite, 1023 

— lygosinate, 605 

— metaoxycyanocinnamate, 669 

— perborate, 966 

— phosphate, 1023 

— salicylate, 672, 677, 1023 

— succinate, 647 

— sulphite, 1026 

— tetraborate, 966 
Solidago species, 396 
Somnos, 590 
Sophol, 726, 974 



1070 



INDEX 



Sorbose, 617 
Sozal, 718 
Soziodol, 719 
Spartein, 94 
Specific gravity, 1 
Spikenard, 329 
Spirosal, 681 
Squawroot, 445 
Squawvine, 444 
Squaw weed, 445 
Squills, assay, 33 

— glucosides of, 323 
Starch, 617 

Sterculia urens, gum of, 469, 470 
Stillingia sylvatica, 432 
Stone root, 442 
Stramonium, assay, 67 
Strontium, 1018 

— salts of, 1018 

— estimation of, 1018 
Strophanthidin, 313 
Strophanthin, 312 
Strophanthus, assay, 67 

— glucosides, 311 

— gratus, 314 

— kombe, 311 

— hispidus, 313 
Strychnin, 252 

— estimation of in presence of quinin, 261 

— determination of in chewing gum, 513 

liquid products, 260 

tablets, 259 

— separation and identification, 258 

of from atropin, 259 

brucin, 259 

Strychnos Nux Vomica, alkaloids of, 250 

— ignatia, 250 
Stovain, 146 

Stylophorum diphyllum, alkaloids of, 244 

Stylopin, 247 

Styracin, 701 

Styracol, 769 

Styrax benzoin, 702 

Subcutin, 144 

Sublamine, 981 

Sucrose, 617 

— determination of, 7 

— estimation of in infant foods, 619 
Sulphonal, 746 

Sugar, cane, estimation of in infant 
foods, 618 

— determination, 7 



Sugar, Munsen and Walker's tables, 10 
Sulphates, estimation of, 956 
Sulphonic acids, 717 
Sulphopyrin, 805 
Sulphur, 954 

— determination of in asafetida oil, 508 

— estimation of, 954 

in compound licorice powder, 410 

— iodide assay, 948 
Sumbul, 435, 631 
Suprarenin, 828 
Swertia chirata, 351 

Tannalbin, 697 
Tannigen, 697 
Tannismuth, 698 
Tannoform, 698 
Tannopin, 584, 698 
Tanosal, 699, 772 
Taraxacum officinale, 450 
Taraxasterol, 450 
Tartar emetic, 1000 

estimation of in plasters, 489 

Tea, estimation of caffein in, 289 
Terebene, 527 
Terpenes, 526 

— sesqui, 526 
Terpin hydrate, 559 
Test, Baudoin, 917 

— Borntrager's, 361 

— Cripp's and Dymond's, 361 

— Elaidin, 641 

— Fluckiger's, 641 

— Halphen's, 915 

— Klunge's, 361 

— Liebermann-Storch, 488 

— Liebermann's, 753, 790 

— Pettenkoffer's, 722 

— Storch-Morawski, 488 

— Villa vecchia, 917 
Tetrahydroquinolin, 815 
Tetraiodophenolphthalein, 667 
Tetronal, 747 

Thalline, 818 
Thapsia garganica, 485 
Thebain, 197 
Theobromin, 291 

— estimation of, 292, 293 
Theophyllin, 294 
Thermin, 811 
Thermodin, 870 

Thial, 585 



INDEX 



1071 



Thioform, 679 
Thioantipyrin, 805 
Thiophene, 747 

— dioxide, 748 

— tetrabromide, 748 
Thiosinamine, 823 
Thiosulphates, estimation of, 956 
Thuja occiden talis, 615 
Thujone, 395, 615 
Thymacetin, 868 
Thyrnoform, 765 

Thymol, 762 

— carbonate, 765 

— ■ estimation of, 763 

— assay, 764 

— iodide, 764 

— salicylate, 765 
Thiocol, 771 
Toluifera periera, 705 

— balsamum, 706 

— pernifera, 706 
Toluylenediamine, 820 
Tolylantipyrin, 805 
Tolypyrin, 794 
Tolysal, 805 
Tragacanth, 468 
Trehalose, 617 
Tribromphenol, 757 
Trichlorethidene propenyl ether, 590 
Trichlorisopropyl alcohol, 743 
Trichlor-tertiary butyl alcohol, 147 
Triferrin, 1011 

Trifolianol, 429 

Trifolin, 430 

Trifolium incarnatum, 428, 431 

— pratense, 428 
Trigemin, 808 
Triiodometacresol, 761 
Trinitrophenol, 756 
Trional, 747 

Trioxybenzophenone, 606 
Trioxymethylene, 575 
Triphenin, 869 
Trisulphoacetylguaiacol, 771 
Triticum, 415 

Tritopin, 196 
Tropacocain, 123 
Tropin, 111 
Truxillin, 122 
Tsuga canadensis, 486 
Tumenol, 721 
Turnera diffusa, 437 



Turpentine, 486 

— chian, 486, 488 

— Russian, 486 

— Venice, 486 
Turpeth, 388 
Tussol, 803 
Tyramin, 301, 830 

Umbelliferone, 435 
Unicorn root, false, 331 

true, 331 

Urea, 822 
Urethane, 824 
Urginea maritima, 323 
Uva-ursi, 334 

Valeriana officinalis, 447, 631 
ValidoL 558 
Valyl, 822 
Vanillin, 597 

— estimation of, 598 
Vellosin, 182 
Veratralbin, 279 
Veratridin, 276 
Veratrin, 274 
Veratrum album, 277 

— assay, 68 

— viride, 277 
Veroform, 580 
Veronal, 826 
Veronica officinalis, 444 

— virginica, 443 
Verosterol, 444 
Viburnum, 631 

— compound, 331 

— opulus, 445 

— prunifolium, 446 
Viferral, 592 
Vioform, 816 
Vitellin, 895, 896 
Vouacapoua araroba, 374 

Wahoo, 433 
Witch hazel, 428 
White pine, 414 
Wild cherry bark, 340 
Wormseed, American, 395 

— Levant, 391 

assay, 64 

Wormwood, 391, 394 

— Roman, 392, 396 



1072 



INDEX 



Xanthalin, 195 
Xanthin, 285 

— bases, determination, 286 

— reactions of, 297 
Xanthoeridol, 441 
Xanthohumulol, 425 
Xanthoxylum americanum, 431 

— clava-herculis, 431 
Xeroform, 757, 994 

Yerba Santa, 438 



Yohimbe Bark, alkaloids of, 178 
Yohimbin, 178 

Zimphen, 669 
Zinc, 1016 

— estimation of, 1017 

— salts of, 1016 
Zinzerone, 405 
Zinziber officinale, 404 
Zygadenin, 274 

Zygadenus intermedium, alkaloids of, 274 




Wiley Special Subject Catalogues 

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